NZ614199B2 - Pyridinyl- and pyrazinyl -methyloxy - aryl derivatives useful as inhibitors of spleen tyrosine kinase (syk) - Google Patents

Pyridinyl- and pyrazinyl -methyloxy - aryl derivatives useful as inhibitors of spleen tyrosine kinase (syk) Download PDF

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NZ614199B2
NZ614199B2 NZ614199A NZ61419912A NZ614199B2 NZ 614199 B2 NZ614199 B2 NZ 614199B2 NZ 614199 A NZ614199 A NZ 614199A NZ 61419912 A NZ61419912 A NZ 61419912A NZ 614199 B2 NZ614199 B2 NZ 614199B2
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methyl
oxy
tetrahydro
phenyl
methylpyridinyl
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Francis Louis Atkinson
Michael David Barker
John Liddle
David Matthew Wilson
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Glaxo Group Limited
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Abstract

Provided are pyridinyl- and pyrazinyl- methyloxy-aryl derivatives of the general formula (I), where the variables are as defined in the specification. Examples of the compounds include 7-(2-(methyloxy)-6-{[(4-methyl-2-pyridinyl)methyl]oxy}phenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine and 7-(5-fluoro-2-{[(4-methyl-2-pyridinyl)methyl]oxylphenyl)-1,2,3,4-tetrahydroisoguinoline. The compounds are inhibitors of spleen tyrosine kinase (Syk). The compounds may be useful in the treatment of autoimmune and/or allergic disorders, particularly dermatological disorders, such as urticaria. -{[(4-methyl-2-pyridinyl)methyl]oxylphenyl)-1,2,3,4-tetrahydroisoguinoline. The compounds are inhibitors of spleen tyrosine kinase (Syk). The compounds may be useful in the treatment of autoimmune and/or allergic disorders, particularly dermatological disorders, such as urticaria.

Description

PYRIDINYL- AND PYRAZINYL -METHYLOXY - ARYL DERIVATIVES USEFUL AS INHIBITORS OF SPLEEN TYROSINE KINASE (SYK) The present invention relates to novel chemical compounds which have activity against spleen tyrosine kinase (Syk), processes for their preparation, pharmaceutically acceptable formulations containing them and their use in therapy.
Syk is a non-receptor tyrosine kinase that is involved in coupling activated immunoreceptors to signal downstream events that mediate diverse cellular responses, including proliferation, differentiation, and phagocytosis. Syk is widely expressed in hematopoietic cells. Syk inhibitors have potential anti-inflammatory and immunomodulating activities. They t Syk-mediated lgG Fc epsilon and gamma receptor and BCR or signalling, resulting in tion of the activation of mast cells, hages, and B-cells and related matory ses and tissue damage. Mast cells play a major role in type | hypersensitivity ons and have been implicated in urticaria, bronchial asthma, laxis and other allergic conditions. Accordingly, Syk inhibitors have attracted interest in a number of therapeutic areas, including the treatment of rheumatoid arthritis, B-cell lymphoma, asthma, rhinitis and cutaneous disorders such as acute and chronic ria, mastocytosis, cutaneous lupus, atopic dermatitis, mune bullous conditions including pemphigus and pemphigoid and other mast cell mediated diseases of the skin.
Acute and chronic urticaria are common skin diseases thought to affect around 25% of the total population within the USA. Although urticaria can be triggered by allergic reactions many cases have an unclear etiology. Chronic urticaria is defined as when wide spread wheals are t for greater than 6 weeks. There are many pathological similarities in chronic urticaria patients, in terms of extent of wheals in the skin, with allergen-induced mast and basophil cell degranulation reactions via lgE activation. Around 40% of chronic urticaria patients contain serum lgG auto- antibodies targeting lgE or the lgE receptor (Fc Epsilon Receptor) and these are thought to drive the histamine and other mediator release via mast and basophil ulation. Syk inhibitors would inhibit the signalling response post lgE ed Fc Epsilon activation and inhibit the mediator e known to be involved in chronic pruritis in multiple diseases. ous mastocytosis is defined as an excessive accumulation of mast cells in the skin normally seen in both the paediatric and adult population. It is a rare disease thought to be due to a dysregulation in the proliferative capacity of the mast cells. 40 The excessive production of mast cells in the skin leads to an increased release of cytokines and histamines which lead to itching, skin lesions, and in some cases where there is a systemic involvement, anaphylactic shock or low blood pressure.
Cutaneous lupus is a condition of the skin found in some patients with a discoid form of lupus erythematosus. The disorder is characterised by a red raised rash on the face or scalp and other areas of the body and mast cells and antibody tion are known to be involved in the lesions.
A Syk tor applied topically would decrease the production of cytokines, histamines and other mediators potentially leading to reduced itching and inflammatory infiltration in the skin.
Atopic dermatitis is a very common and sometimes long lasting inflammatory skin disorder characterised by redness and pruritis. The disease often occurs with other allergic conditions such as hay fever or asthma, is found predominantly in young children and is exacerbated by contact with allergens. Mast cell involvement is understood to lead to the characteristic itching and excessive scratching which can lead to an increase in bacterial infections in the skin. l application of a Syk inhibitor could reduce these symptoms.
Autoimmune bullous conditions including pemphigus and pemphigoid are acute and chronic skin diseases involving the formation of blisters. Bullous pemphigoid (BP) is a c, autoimmune, subepidermal, blistering skin disorder (unlike pemphigus where the blistering is intraepidermal). These rare diseases lly affect people over the age of 70. Autoantibodies are generated against the basement membrane layer of the skin leading to activation of complement and other inflammatory ors. The inflammatory s initiates a release of enzymes which degrade proteins in the hemidesmosomal layers eventually leading to blisters as the layers of the skin fall apart. An urticarial rash and pruritis generally occur prior to onset of the blisters, so inhibition of mast cell degranulation and cytokine production post lgG antibody activation in hages with a Syk inhibitor could be cial in these diseases.
Rheumatoid arthritis (RA) is an autoimmune disease affecting approximately 1% of the population. It is characterised by inflammation of articular joints leading to debilitating destruction of bone and age. Recent al studies with rituximab, which causes a reversible B cell depletion, (J.C.W. Edwards et al 2004, New Eng. J.
Med. 350: 581), have shown that targeting B cell on is an appropriate therapeutic gy in autoimmune diseases such as RA. Clinical t correlates with a reduction in auto-reactive antibodies (or rheumatoid Ffactor) and these studies suggest that B cell function and indeed auto-antibody production are central to the ongoing pathology in the disease 40 Studies using cells from mice deficient in Syk have demonstrated a non-redundant role of this kinase in B cell function. The deficiency in Syk is characterised by a block in B cell development (M. Turner et al 1995 Nature 379: 298-302 and Cheng et al 1995, Nature 378: 303-306). These studies, along with studies on mature B cells deficient in Syk (Kurasaki et al 2000, lmmunol. Rev. 176:19-29), demonstrate that Syk is required for the differentiation and activation of B cells. Hence, inhibition of Syk in RA patients is likely to block B cell on and hence reduce rheumatoid factor production. In addition to the role of Syk in B cell function, of relevance to the treatment of RA, is the requirement for Syk activity in Fc receptor (FcR) signalling.
FcR tion by immune complexes in RA has been suggested to bute to the release of multiple pro-inflammatory ors.
The contribution of Syk dependent processes to the pathology of RA has been reviewed by Wong et al (2004, ibid).
The results of a 12 week proof of concept clinical trial for the Syk inhibitor R788 (fostamatinib disodium, Rigel) have been hed: Treatment of rheumatoid arthritis with a Syk inhibitor: A twelve-week, randomized, placebo-controlled trial, Arthritis & Rheumatis, 58(11), 2008, 3309-3318.
Syk inhibitors may also be useful in cancer therapy, ically heme malignancies, particularly dgkin’s Lymphomas including ular (FL), mantle cell, Burkitt and diffuse large B cell (DLBCL) lymphomas.
Studies have shown that Syk is dysregulated by overexpression and/or constitutively activation in a variety of primary B-Iymphoma tumours and also in B-Iymphoma cell lines. Syk, through the PI3K / AKT pathway, the PLD pathway and AKT independent signalling, activates mTOR (mammalian target of rapamycin) which in turn increases B-cell survival and proliferation. tion of Syk in vitro, results in decreased mTOR activation and a reduction of clonicity in FL cells. Inhibition of Syk with curcumin in a murine model of B lymphoma (BKS-2) gave a significant reduction of tumour burden as measured by the total splenocyte number. (Leseux L. et al. Blood 15 Dec 2006, Vol 108, No 13 pp 4156-4162 and Gururajan M. et al. l of Immunology, 2007, 178 pp 111-121).
Results of a Phase 2 clinical trial of R788 (fostamatinib disodium) in patients with relapsed or refractory B-Cell non-Hodgkin's lymphoma (NHL) show that the compound is well-tolerated by these patients, as well as a therapeutic benefit in patients suffering from diffuse large B-Cell lymphoma (DLBCL) and c Iymphocytic leukemia/small Iymphocytic lymphoma (CLL/SLL). Despite the fact that the patients enrolled in this trial had advanced disease and had failed treatment with marketed therapies, a icant number of them were particularly responsive to Syk inhibition with R788 (Chen et al Blood 2008 Vol 111 pp 237, www.Rigel.com) 40 Syk inhibitors may also be useful in the treatment of asthma and ic is as they are important in transducing the downstream cellular signals associated with cross-linking FcaR1 and or FCyR1 receptors, and Syk is oned early in the signalling cascade. In mast cells, for example, the early sequence of FcaR1 2012/053948 signalling following allergen cross-linking of receptor-lgE complexes involves first Lyn (a Src family tyrosine kinase) and then Syk.
Allergic rhinitis and asthma are diseases associated with hypersensitivity reactions and inflammatory events involving a multitude of cell types including mast cells, eosinophils, T cells and dendritic cells. Following re to allergen, high affinity immunoglobulin receptors for lgE (FcaRl) and IgG (FCyRI) become cross-linked and activate downstream processes in mast cells and other cell types leading to the release of pro-inflammatory mediators and airway spasmogens. In the mast cell, for example, lgE receptor cross-linking by allergen leads to e of mediators including histamine from pre-formed granules, as well as the synthesis and release of newly synthesised lipid mediators including prostaglandins and leukotrienes.
The Syk inhibitor R112 ), dosed intranasally in a phase II” study for the treatment of allergic rhinitis, was shown to give a statistically significant decrease in PGDg, a key immune mediator that is highly correlated with improvements in allergic rhinorrhea, as well as being safe across a range of indicators, thus providing the first ce for the al safety and efficacy of a l Syk inhibitor (see Meltzer, Eli O.; Berkowitz, Robert B.; Grossbard, Elliott B. An intranasal Syk inhibitor (R112) improves the symptoms of seasonal allergic rhinitis in a park environment. Journal of Allergy and Clinical Immunology (2005), 115(4), 791-796). In a r phase II clinical trial, for allergic rhinitis, R112 was however shown as having a lack of efficacy versus o (Clinical Trials.gov Identifier NCT0015089).
WO 03/057695 (Boehringer Ingelheim Pharmaceuticals, Inc) describes 1,6 Naphthyridines that have Syk tory activity. These are further described in very and SAR of Novel [1 ,6] yridines as Potent tors of Spleen Tyrosine Kinase (SYK) (Bioorganic & Medicinal Chemistry Letters 13 (2003) 1415 — 1418). This has been followed with two more recent patent applications, WO 2010/015518 and inger Ingelheim Pharmaceuticals, Inc), describing 4-dimethylamino-phenyl-substituted naphthyridines and substituted naphthyridines, respectively.
WO 04/035604 discloses the structural co-ordinates of the human Syk protein.
There remains however the need to identify further compounds which are inhibitors of Syk.
Description of the drawings 40 Figure 1 shows the XRPD ction pattern for FORM 1.
Figure 2 showns the FT-Raman Spectrum for FORM 1.
Figure 3 shows the DSC thermogram of FORM 1.
Figure 4 shows the XRPD diffraction pattern for FORM 2.
Figure 5 shows the en Spectrum for FORM 2.
Figure 6 shows DSC thermogram of FORM 2.
Description of the Invention Thus, in one embodiment, the present invention provides a compound of formula (I): wherein: X is CR1 or N; Y is CH, C or N; R1 is hydrogen, C1_6alkoxy or C1_6alkyl; R2 is hydrogen, C1_6alkoxy, halo, -C(O)C1_6alkyl, CN, Halo-C1_6alkyl or C(O)NR4R5; R3 is hydrogen or C1_6alkoxy; R4 is hydrogen or C1_6alkyl: R5 is en or C1_6alkyl and m and n are integers each independently ed from 1 and 2; or a salt thereof.
In one embodiment, the invention es a nd of formula (la); wherein: X is CR1 or N; Y is CH, C or N; R1 is hydrogen, C1_6alkoxy or C1_6alkyl; R2 is hydrogen, C1_6alkoxy, halo or -C(O)C1_6alkyl; and m and n are integers each independently selected from 1 and 2; or a salt thereof.
In one embodiment X is CR1 or N. In another embodiment X is CR1.
In one embodiment Y is CH, C or N. In another embodiment Y is CH. In another embodiment Y is C. In a further ment Y is N.
In one ment R1 is hydrogen, C1_6alkoxy or C1_6alkyl. In another embodiment R1 is methyl, methoxy or hydrogen.
In one embodiment R2 is hydrogen, C1_6alkoxy, halo, -C(O)C1_6alkyl, CN, Halo-C1_6_ alkyl or C(O)NR4R5. In one embodiment R2 is hydrogen, C1_6alkoxy, halo or -C(O)C1_ . In another embodiment R2 is hydrogen, methoxy, fluoro, -C(O)CH3 or trifluoromethyl. In another embodiment R2 is hydrogen, methoxy, fluoro or H3.
In a further embodiment R2 is hydrogen, methoxy or -C(O)CH3.
In one embodiment R3 is hydrogen or C1_6alkoxy. In one embodiment R3is hydrogen, or methoxy.
In one embodiment R4 is hydrogen or C1_6alkyl. In another embodiment R4 is hydrogen or CMalkyl. In a r embodiment R4 is hydrogen or .
In one embodiment R5 is hydrogen or C1_6alkyl. In another embodiment R5 is hydrogen or CMalkyl. In a r embodiment R5 is hydrogen or methyl.
In one ment m and n are integers each independently selected from 1 and 2.
In r embodiment m is 2 and n is 1 or 2. In another embodiment n is 1 and m is 1 or 2. In a further embodiment m and n are both 2.
In one embodiment X is CR1, and R1 is methyl. In another embodiment, X is CR1, R1 is methyl and Y is C. In a further embodiment, X is CR1, R1 is methyl, Y is C and R2 is methoxy. In a yet r embodiment, X is CR1, R1 is methyl, Y is C, R2 is methoxy and R3 is hydrogen. In a still further embodiment, X is CR1, R1 is , Y is C, R2 is methoxy, R3 is hydrogen, m is 2 and n is 2.
In one embodiment, the compound of formula (I) is selected from: 7-(3-{[(4-methylpyridinyl)methyl]oxy}pyridinyl)—2,3,4,5-tetrahydro-1H benzazepine; 7-(2-(methyloxy)-6—{[(4-methylpyridinyl)methyl]oxy}phenyl)—2,3,4,5-tetrahydro—1 H- 3-benzazepine; 7-(4-(methyloxy){[(4-methylpyridinyl)methyl]oxy}phenyl)—2,3,4,5-tetrahydro—1 H- 40 3-benzazepine; 1-[4-{[(4-methylpyridinyl)methyl]oxy}(2,3,4,5-tetrahydro—1Hbenzazepin yl)phenyl]ethanone; 7-(6—methyl{[(4-methylpyridinyl)methyl]oxy}pyridinyl)—2,3,4,5-tetrahyd ro-1 H benzazepine; (2-pyrazinylmethyl)oxy](2,3,4,5-tetrahydro—1Hbenzazepin y|)pheny|]ethanone; 7-(5-fluoro—2—{[(4-methyl-2—pyridinyl)methy|]oxy}pheny|)-1,2,3,4- tetrahydroisoquinoline; ethyl-2—{[(4-methyl-2—pyridinyl)methyl]oxy}pheny|)—1,2,3,4- tetrahydroisoquinoline; 7-(2—(methy|oxy)—6—{[(4-methyl-2—pyridiny|)methy|]oxy}phenyI)-1 ,2,3,4- tetrahydroisoquinoline; 7-(5-(ethyloxy)-2—{[(4-methyIpyridinyl)methyl]oxy}phenyI)-1,2,3,4- tetrahydroisoquinoline; methy|oxy)—2—{[(4-methyl-2—pyridiny|)methy|]oxy}phenyI)-1 ,2,3,4- tetrahydroisoquinoline; 4-{[(4-methyl-2—pyridinyl)methyl]oxy}(1 ,2,3,4-tetrahyd ro—7- isoquinolinyl)benzonitrile; 7-[2—{[(4-methy|—2—pyridinyl)methy|]oxy}(trif|uoromethy|)phenyI]-1,2,3,4- tetrahydroisoquinoline; 7-(5-(methy|oxy)—2—{[(4-methyl-2—pyridinyl)methy|]oxy}phenyI)-1,2,3,4- tetrahydroisoquinoline; 7-(5-(1,1-dimethylethyl){[(4-methy|—2—pyridinyl)methyl]oxy}phenyI)-1,2,3,4- tetrahydroisoquinoline; N-methyI{[(4-methyl-2—pyridinyl)methyl]oxy}(2,3,4,5-tetrahydro—1H benzazepinyl)benzamide; 4-{[(4-methyl-2—pyridinyl)methyl]oxy}(2,3,4,5-tetrahyd ro—1 Hbenzazepin y|)benzamide; N,N-dimethyl{[(4-methyl-2—pyridinyl)methyl]oxy}(1,2,3,4-tetrahydro—7- isoquinolinyl)benzamide; 4-{[(4-methyl-2—pyridinyl)methyl]oxy}(1,2,3,4-tetrahydro—7-isoquinolinyl)benzamide; -bis(methyloxy)—6—{[(4-methyl-2—pyridinyl)methyl]oxy}phenyl)-1 ,2,3,4- tetrahydroisoquinoline; 7-(2,3-bis(methyloxy)—6—{[(4-methy|—2—pyridinyl)methyl]oxy}pheny|)-2,3,4,5-tetrahydro- 1Hbenzazepine; 7-[2—({[4-(methyloxy)—2—pyridinyl]methy|}oxy)pheny|]—2,3,4,5-tetrahydro—1 H benzazepine; 1-[4-[(2-pyridinylmethyl)oxy](2,3,4,5-tetrahyd ro—1 Hbenzazepin y|)pheny|]ethanone, trifluoroacetate; 7-{6—methyl[(2—pyrazinylmethyl)oxy]pyridiny|}-2,3,4,5-tetrahydro—1 H benzazepine, trifluoroacetate ; 7-(6—methyl{[(4-methyl-2—pyridinyl)methyl]oxy}-2—pyridinyl)—2,3,4,5-tetrahyd ro—1 H epine, trifluoroacetate; 40 7-{5-(methyloxy)—2—[(2—pyrazinylmethyl)oxy]phenyI}-2,3,4,5-tetrahyd ro—1 H benzazepine, trifluoroacetate ; 7-[5-(methyloxy)—2—({[4-(methyloxy)—2—pyridinyl]methyl}oxy)phenyl]—2,3,4,5-tetrahydro— 1Hbenzazepine; WO 23311 7-(5-(methonxy)—2—{[(4-methy|—2—pyridinyl)methyl]oxy}pheny|)—2,3,4,5-tetrahydro—1 H- 3-benzazepine, trifluoroacetate; 1-[4-({[4-(methyloxy)—2—pyridinyl]methyl}oxy)—3-(2,3,4,5-tetrahyd ro—1 Hbenzazepin- 7-yl)phenyl]ethanone; 1-[4-{[(4-methy|—2—pyridinyl)methyl]oxy}(2,3,4,5-tetrahydro—1Hbenzazepin y|)pheny|]ethanone, trifluoroacetate; 7-[2—({[4-(methyloxy)—2—pyridinyl]methy|}oxy)pheny|]—2,3,4,5-tetrahydro—1 H benzazepine, trifluoroacetate; 1,1-dimethylethyl 7-[6—methyl({[4-(methyloxy)—2—pyridinyl]methyl}oxy)—2—pyridiny|]- 1 ,2,4,5-tetrahyd ro—3Hbenzazepine—3-carboxylate; 7-(5-fluoro—2—{[(4-methyl-2—pyridinyl)methyl]oxy}phenyl)—2,3,4,5-tetrahydro—1 H epine; 7-(5-methyl-2—{[(4-methy|—2—pyridinyl)methyl]oxy}pheny|)—2,3,4,5-tetrahyd ro—1 H benzazepine; 7-(5-(ethyloxy)-2—{[(4-methyIpyridinyl)methyl]oxy}pheny|)—2,3,4,5-tetrahyd ro—1 H benzazepine; 7-(5-(methonxy)—2—{[(4-methy|—2—pyridinyl)methyl]oxy}pheny|)—2,3,4,5-tetrahydro—1 H- 3-benzazepine; -methyl-2—pyridinyl)methyl]oxy}(2,3,4,5-tetrahyd ro—1 Hbenzazepin y|)benzonitri|e 7-[2—{[(4-methy|—2—pyridinyl)methy|]oxy}(trif|uoromethyl)phenyl]—2,3,4,5-tetrahydro— 1Hbenzazepine; 7-(5-(1,1-dimethylethyl){[(4-methy|—2—pyridinyl)methyl]oxy}pheny|)—2,3,4,5- tetrahydro—1Hbenzazepine; 7-(5-ch|oro—2—{[(4-methyl-2—pyridinyl)methyl]oxy}pheny|)—2,3,4,5-tetrahydro—1 H benzazepine; [(4-ethy|—2—pyridinyl)methyl]oxy}-6—methyl-2—pyridinyl)—2,3,4,5-tetrahyd ro—1 H benzazepine 7-(6—(1,1-dimethylethyl){[(4-methy|—2—pyridinyl)methyl]oxy}-2—pyridinyl)—2,3,4,5- tetrahydro—1Hbenzazepine; 1-[4-{[(4-ethy|—2—pyridinyl)methy|]oxy}(2,3,4,5-tetrahydro—1Hbenzazepin y|)pheny|]ethanone; 1-[4-({[4-(ethy|oxy)—2—pyridinyl]methyl}oxy)—3-(2,3,4,5-tetrahydro—1Hbenzazepin y|)pheny|]ethanone; 1-[4-{[(4-{[2—(methyloxy)ethy|]oxy}-2—pyridinyl)methyl]oxy}(2,3,4,5-tetrahyd ro—1 H benzazepinyl)phenyl]ethanone; 7-{5-(methyloxy)—2—[(2—pyridinylmethyl)oxy]phenyI}-2,3,4,5-tetrahydro—1 H benzazepine; 1-[4-[(2-pyridinylmethyl)oxy]—3-(1,2,3,4-tetrahydro—7-isoquinolinyl)phenyl]ethanone; 40 7-{5-chloro[(2-pyridinylmethyl)oxy]phenyI}-1,2,3,4-tetrahydroisoquinoline; 7-(6—ch|oro—3-{[(4-methyl-2—pyridinyl)methyl]oxy}-2—pyridiny|)-2,3,4,5-tetrahydro—1 H benzazepine; 7-(6—ch|oro—3-{[(4-methyl-2—pyridinyl)methyl]oxy}-2—pyridiny|)-1 ,2,3,4- tetrahydroisoquinoline; 1,1-dimethylethyl 5-{5-acetyl-2—[(2—pyridinylmethyl)oxy]phenyl}-1,3-dihydro-2H- isoindolecarboxylate; 1-[4-[(2-pyridinylmethyl)oxy]—3-(1,2,3,4-tetrahydro-6—isoquinolinyl)phenyl]ethanone; 7-{2—(methyloxy)—6—[(2—pyrazinylmethyl)oxy]phenyl}-2,3,4,5-tetrahyd ro-1 H benzazepine, hloride; or a salt thereof.
In one embodiment, the compound of formula (I) is selected from: 7-(3-{[(4-methylpyridinyl)methyl]oxy}-2—pyridinyl)—2,3,4,5-tetrahyd ro-1 H benzazepine; 7-(2—(methyloxy)-6—{[(4-methyl-2—pyridinyl)methyl]oxy}phenyl)—2,3,4,5-tetrahydro—1 H- 3-benzazepine; 7-(4-(methyloxy)-2—{[(4-methyl-2—pyridinyl)methyl]oxy}phenyl)—2,3,4,5-tetrahydro—1 H- 3-benzazepine; 1-[4-{[(4-methyl-2—pyridinyl)methyl]oxy}(2,3,4,5-tetrahydro—1Hbenzazepin yl)phenyl]ethanone; 1-[4-[(2-pyrazinylmethyl)oxy](2,3,4,5-tetrahydro-1Hbenzazepin yl)phenyl]ethanone; 7-(5-fluoro{[(4-methylpyridinyl)methyl]oxy}phenyl)—1,2,3,4- ydroisoquinoline; 7-[2—({[4-(methyloxy)—2—pyridinyl]methyl}oxy)phenyl]—2,3,4,5-tetrahydro—1 H benzazepine; and 1-[4-[(2-pyridinylmethyl)oxy]—3-(2,3,4,5-tetrahydro-1Hbenzazepin yl)phenyl]ethanone; or a salt f.
In one embodiment the compound of formula (I) is: 7-(3-{[(4-methylpyridinyl)methyl]oxy}-2—pyridinyl)—2,3,4,5-tetrahyd ro-1 H benzazepine; or a salt thereof.
In another embodiment the compound of formula (I) is: 7-(2—(methyloxy)-6—{[(4-methyl-2—pyridinyl)methyl]oxy}phenyl)—2,3,4,5-tetrahydro—1 H- 3-benzazepine; or a salt thereof.
In another embodiment the compound of formula (I) is: 7-(4-(methyloxy)-2—{[(4-methyl-2—pyridinyl)methyl]oxy}phenyl)—2,3,4,5-tetrahydro—1 H- 3-benzazepine; or a salt thereof.
In a r ment the compound of formula (I) is: 1-[4-{[(4-methyl-2—pyridinyl)methyl]oxy}(2,3,4,5-tetrahydro—1Hbenzazepin yl)phenyl]ethanone; or a salt thereof.
It will be iated in the following that the phrase “a nd of formula (I)” is intended to include a compound of formula (la).
It will be appreciated that nds of a (I) and salts thereof may exist in solvated forms. In another embodiment, the present invention provides compounds of formula (I) and salts thereof. In another embodiment, the present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof. In another ment, the present invention provides nds of formula (I) and solvates thereof. In a further ment, the present invention provides compounds of formula (I) as the free base.
Compounds of the present invention are useful as inhibitors of Syk.
As used herein, the term “alkyl” refers to a straight or branched saturated hydrocarbon chain ning the specified number of carbon atoms. For example, C1_6alkyl means a straight or ed alkyl group containing at least 1, and at most 6, carbon atoms. Examples of “alkyl” as used herein include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isobutyl, isopropyl, t-butyl and 1,1- dimethylpropyl.
As used herein, the term “alkoxy” refers to a straight or branched saturated alkoxy chain containing the specified number of carbon atoms. For example, C1_6alkoxy means a straight or branched alkoxy group ning at least 1, and at most 6, carbon atoms. Examples of “alkoxy” as used herein include, but are not limited to, methoxy, ethoxy, propoxy, propoxy, butoxy, butoxy, 2—methylpropoxy, 2- methylpropoxy, pentoxy or hexyloxy.
As used herein, the term “halo” or, alternatively, “halogen” refers to fluoro, chloro or bromo.
As used herein, the term “haloalkyl” refers to a straight or ed saturated hydrocarbon chain containing the specified number of carbon atoms, substituted with halo atoms. For example, Halo-C1_6alkyl means a straight or branched alkyl group containing at least 1, and at most 6, carbon atoms, substituted with 1 to 3 halo atoms per carbon atom. Examples of “haloalkyl” as used herein include, but are not limited to, fluoromethyl, di-fluoromethyl, and tri-fluoromethyl. 40 As used herein, the term aceutically acceptable” refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical nt, le for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problems or cations, commensurate with a reasonable benefit/risk ratio. The skilled artisan will appreciate that pharmaceutically acceptable salts of the compound of a (I) may be prepared.
As used herein, the term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, tively. Indeed, in n embodiments of the invention, pharmaceutically able salts may be preferred over the respective free base or free acid e such salts impart greater ity or lity to the molecule thereby facilitating formulation into a dosage form.
The compounds of formula (I) are basic and accordingly generally capable of forming pharmaceutically acceptable acid addition salts by ent with a suitable acid.
Suitable acids include pharmaceutically acceptable nic acids and pharmaceutically acceptable organic acids. Representative pharmaceutically acceptable acid addition salts include hydrochloride, hydrobromide, nitrate, methylnitrate, sulfate, bisulfate, sulfamate, phosphate, acetate, hydroxyacetate, phenylacetate, propionate, butyrate, isobutyrate, valerate, maleate, hydroxymaleate, acrylate, fumarate, malate, tartrate, citrate, salicylate, p-aminosalicyclate, glycollate, lactate, heptanoate, phthalate, oxalate, succinate, benzoate, o-acetoxybenzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, mandelate, tannate, formate, stearate, ascorbate, palmitate, oleate, pyruvate, pamoate, malonate, laurate, glutarate, glutamate, estolate, methanesulfonate (mesylate), ethanesulfonate (esylate), 2—hydroxyethanesulfonate, benzenesulfonate (besylate), p—aminobenzenesulfonate, enesulfonate (tosylate),napthalene—2—sulfonate, Ethanedisulfonate, and 2,5-dihydroxybenzoate,. In one embodiment, the present invention provides a pharmaceutically acceptable salt of a compound of formula (I) which is the hydrochloride salt, mesylate, fumarate or phosphate. In one embodiment, the present invention provides a pharmaceutically able salt of a compound of formula (I) which is the mesylate.
A compound of formula (I) may exist in solid or liquid form. In the solid state, the compound of formula (I) may exist in crystalline or non-crystalline (amorphous) form, or as a mixture thereof. For a compound of formula (I) that is in crystalline form, the skilled artisan will appreciate that solvates, such as pharmaceutically acceptable solvates, may be formed wherein solvent molecules are incorporated into the crystalline e during crystallization. Solvates may e ueous solvents 40 such as, but not limited to, ethanol, isopropanol, n-butanol, nol, acetone, ydrofuran, dioxane, DMSO, acetic acid, ethanolamine, and ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice.
Solvates wherein water is the solvent incorporated into the crystalline lattice are lly referred to as "hydrates". Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water.
The skilled n will further appreciate that a compound of formula (I) that exists in crystalline form, including the various solvates f, may exhibit polymorphism (i.e. the capacity to occur in different crystalline structures). These different crystalline forms are typically known as "polymorphs." The invention includes all such polymorphs. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the lline solid state. Polymorphs, therefore, may have ent physical properties such as shape, density, hardness, deformability, ity and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder ction patterns, which may be used for identification. The skilled artisan will appreciate that different polymorphs may be ed, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.
In a further , the present invention provides a crystalline form of 7-(2- (methyloxy){[(4-methylpyridinyl)methyl]oxy}phenyl)-2,3,4,5-tetrahydro-1H benzazepine (FORM 1) characterised by substantially the same X-ray powder diffraction (XRPD)pattern as shown in Figure 1, wherein the XRPD n is expressed in terms of 2 theta angles and obtained with a diffractometer using copper Kor—radiation using procedures described herein. The XRPD of FORM 1 shows characteristic 2 theta angle peaks at 11.7, 12.7, 13.7 and 16.0.
Alternatively or onally, FORM 1 of 7-(2-(methyloxy)—6-{[(4-methyl pyridinyl)methyl]oxy}phenyl)-2,3,4,5-tetrahydro-1Hbenzazepine can be characterised by Raman spectroscopy as shown in Figure 2, wherein the spectrum is expressed in terms of cm'1 and obtained using procedures as herein described. The Raman spectrum of FORM 1 has characteristic peaks at 2945, 2832, 1610, 1363, 994 and 784. atively or additionally, FORM 1 of methyloxy)—6-{[(4-methyl pyridinyl)methyl]oxy}phenyl)-2,3,4,5-tetrahydro-1Hbenzazepine can be characterised by differential scanning calorimitry (DSC) thermograms as shown in Figure 3, wherein the DSC was performed using procedures as herein described.
In a further aspect, the present invention provides a crystalline form of 7-(2- (methyloxy)—6-{[(4-methylpyridinyl)methyl]oxy}phenyl)—2,3,4,5-tetrahyd ro-1 H benzazepine (FORM 2) terised by substantially the same X-ray powder diffraction (XRPD)pattern as shown in Figure 4, wherein the XRPD pattern is expressed in terms of 2 theta angles and obtained with a diffractometer using copper Kor-radiation using procedures described herein. The XRPD of FORM 1 shows characteristic 2 theta angle peaks at 8.9, 9.9, 13.3, 15.2, 16.7. atively or additionally, FORM 2 of 7-(2-(methyloxy)—6-{[(4-methyl pyridinyl)methyl]oxy}phenyl)—2,3,4,5-tetrahydro-1Hbenzazepine can be characterised by Raman spectroscopy as shown in Figure 5, n the spectrum is expressed in terms of cm'1 and obtained using procedures as herein described. The Raman spectrum of FORM 1 has characteristic peaks at 2934, 1614, 1371, 1005 and 777.
Alternatively or additionally, FORM 2 of methyloxy)—6-{[(4-methyl pyridinyl)methyl]oxy}phenyl)—2,3,4,5-tetrahydro-1Hbenzazepine can be characterised by differential scanning calorimitry (DSC) thermograms as shown in Figure 6, wherein the DSC was performed using methods as described herein.
A compound of formula (I) may be prepared by the general synthetic schemes described after.
Scheme 1: 0/3 O F3COj/Om g: PdCI2—>dppf.CH2C|2 N—< < dppf/ KOAc / dioxane 0% pinacol diborane Scheme 2: wherein Y, R1 and R2 are as before defined.
Step A: Potassium carbonate / DMF Step B: PdCI2.dppf/ caesium carbonate / aqueous dioxane / heat; or tetrakis / sodium carbonate / aqueous DME / heat Step C: HCI in dioxane; or trifluoroacetic acid in dich|oromethane Scheme 3: N\ O \ Br “W I 04% I / O / CI Step A N N Step B O O N >T NH Step A: Potassium carbonate / DMF Step B: is / sodium carbonate / aqueous DME / heat Step C: HCI in dioxane; or trifluoroacetic acid in dichloromethane Scheme 4: fill/0m 0 ——F—>Bj\/OStep A O\©\I:OBStep B HCI salt NJOLOJ< 61 StepC d O N/ O N/ O F O Step A: Potassium carbonate / DMF Step B: PdCI2.dppf/ m carbonate / aqueous dioxane / heat Step C: HCI in dioxane; or trifluoroacetic acid in dichloromethane Scheme 5: CH O Step A \ Step B Step C ——> I ———> / N /N /N OH OH Step D Br \ \ ———> Step A: Potassium carbonate / DMF / benzyl bromide Step B: N /thf/tert-butylmagnesium chloride (in thf) Step C: 20% Pd(OH)2 / H2 / EtOH Step D: Bromine / pyridine Scheme 6: X\ Br HO —> I 1/ \ / O N —R2 | I—R2 Step A: DEAD / PPh3 / thf Scheme 7: N/ N/ OH Step A: Ammonium peroxydisulfate / conc. Sulphuric acid / aqueous methanol Scheme 8: Step A R OH N\ Step A: EDC / HOBT/TEA/ DCM / RRgNH Scheme 9: Step A OH NH2 Step A: (i) DCM / DMF / oxalyl chloride. (ii) NH3 Scheme 10: HOUO\ \ StepB StepA ©: o/ 0/ Br Br /O\/O 0\ HO O Step C / o/ \ Step A: chloromethyl methyl ether/ DIPEA/ DCM Step B: (i) TMEDA/ tert—BuLi /Et20 (ii) Bromine Step C: Conc. Hydrochloric acid / methanol Scheme 11 HO Ste A \ N p | —> \ N Step A: bromine / pyridine Scheme 12 HO Step A Step A: Bromine / chloroform Scheme 13 N k N X CI o’R Step A / o I N d// O Step A: KOtBu / ROH / 110°C Scheme 14 Alternative synthesis to Example 2, mesylate salt \ n.BuI_I/ iPngCI NaBH4 SOCI2 N’ B, N/ /O—>MeOHHam NHCI Stage 1 Stage 2 Stage 3 952 03200a DMF \ Br —> | / 0 OMG Mezso4 Stage 7 OH OH NaOH NaZSO3 NaH003 Brz, EtOH, ACOH Br Br MeOH water IHZH water OH Stage 4 OH Stage 5 stage 6 POO £300 bis(pinacol))borane N “29 PEPPSI-IPr N KOAC p0“ pyrIdIne toluene, EtOH Pd(OAC)2 DOM aq KOH DMSO Stage 8 Stage 9 Stage 10 , NH N .MeSOaH .MeSO3H MeSO3H CW5 at II''33 '°”t' IPA/water \ O | OMe —> I o OMe / o OMe N/ N 0 Stage 11 Stage 12 WO 23311 Thus, in a r aspect, the present invention es a process for preparing a compound of formula (I) which process comprises reacting a compound of formula (II): N/ O wherein X, Y and R2 are as hereinbefore defined; with a c ester or acid of formula (III): R6\O/B\ /R70 (III) wherein R6 and R7 which may be the same or different are each hydrogen, C1_6alkyl or R6 and R7 may be joined to form a C1_3alkylene group ally substituted by up to four methyl groups, for instance —C(Me)zC(Me)2-; P is a protecting group; and m and n are as hereinbefore d; in the presence of a catalyst, under conditions typically used for a boronic ester/acid coupling; and thereafter, removing any protecting group.
Conditions typically used for a boronic ester/acid coupling includes the use of the Pd(PPh3)4 as catalyst, with caesium carbonate in a solvent such as aqueous 1,4- dioxane. Alternatively conditions that could be used include the use of PEPPSITM as catalyst, with potassium ide in a solvent such as aqueous dimethoxyethane (DME) with ethanol.
Examples of protecting groups and the means for their removal can be found in T. W.
Greene ‘Protective Groups in Organic sis’ (J. Wiley and Sons, 1991). Suitable amine protecting groups include, but are not restricted to, sulphonyl (such as tosyl), acyl (such as benzyloxycarbonyl or t-butoxycarbonyl) and arylalkyl (such as benzyl), which may be removed by hydrolysis or enolysis as appropriate. Other suitable amine protecting groups include oroacetyl (-C(O)CF3), which may be removed by base catalysed hydrolysis, or a solid phase resin bound benzyl group, such as a Merrifield resin bound 2,6—dimethoxybenzyl group (Ellman linker) which may be removed by acid catalysed hydrolysis (using, for example, oroacetic acid).
In one embodiment of the present invention the protecting group (P) is selected from utyloxycarbonyl “BOC” and 9-fluorenylmethyloxycarbonyl “FmoC”.
Compounds of formula (I) are useful as inhibitors of Syk and thus potentially of use in treating some cancer therapies, in particular heme malignancies, as well as inflammatory conditions which involve B cells, and also diseases resulting from opriate mast cell activation, for instance allergic and inflammatory diseases such as cutaneous mast cell mediated diseases including acute and chronic urticaria, mastocytosis, atopic dermatitis and autoimmune diseases such as cutaneous lupus and autoimmune bullous conditions including pemphigus and pemphigoid.
In one aspect, the present invention es a compound of a (I) or a pharmaceutically acceptable salt thereof, for use in therapy.
In another aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt f, for use in inhibiting spleen tyrosine kinase (Syk)- In a further aspect, the present invention provides a method comprising administering to a t, particularly a human subject in need thereof an effective amount of a nd of formula (I) or a pharmaceutically acceptable salt thereof, to inhibit a spleen tyrosine kinase (Syk).
Syk inhibitors may be useful in cancer therapy, specifically heme malignancies, particularly Non-Hodgkin’s Lymphomas including follicular (FL), mantle cell, small lymphocytic lymphoma/chronic lymphocytic lymphoma (SLL/CLL), Burkitt and diffuse large B cell (DLBCL) lymphomas. Syk inhibitors may also be useful in the treatment of Acute d leukaemia and retinoblastoma.
In one aspect, the present invention es a nd of a (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, for example, Acute myeloid leukaemia, retinoblastoma, heme malignancies, particularly Non-Hodgkin’s lymphomas including follicular (FL), mantle cell, small lymphocytic lymphoma/chronic lymphocytic lymphoma (SLL/CLL), t and diffuse large B cell (DLBCL) lymphomas.
In another , the present ion provides a method of treating cancer, for 40 example, Acute myeloid leukaemia, retinoblastoma, heme malignancies, particularly Non-Hodgkin’s Lymphomas ing follicular (FL), mantle cell, small cytic lymphoma/chronic lymphocytic lymphoma (SLL/CLL), Burkitt and diffuse large B cell (DLBCL) lymphomas, which method comprises administering to a subject, particularly a human t in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
In a further aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer, for example, Acute myeloid leukaemia, retinoblastoma, heme malignancies, particularly Non-Hodgkin’s lymphomas including follicular (FL), mantle cell, small lymphocytic lymphoma/chronic lymphocytic lymphoma (SLL/CLL), Burkitt and diffuse large B cell (DLBCL) lymphomas.
Compounds of formula (I) may also be used in cancer chemotherapy in combination with other classes of cancer chemotherapy agents which are known in the art.
Representative classes of agents for use in such combinations for Non-Hodgkin’s Lymphomas include rituximab, BEXXAR (tositumomab and lodine l 131 tositumomab) and pixantrone. Compounds of the Formula (I) may also be used in combination with the CHOP drug regime (cyclophosphamide, adriamycin, vincristine, prednisone) or CHOP plus rituximab R).
Compounds of formula (I) are potentially of use in treating autoimmune conditions which e B cells and/or macrophage activation, for example systemic lupus erythematosus (SLE), discoid (cutaneous) lupus, Sjorgens syndrome, Wegners granulomatosis and other itides, bullous goid and pemphigus, idiopathic thrombocytopenic purpura (ITP), giant cell arteriosis, chronic idiopathic urticaria with and without auto-antibody status (chronic autoimmune ria (New concepts in chronic urticaria, Current Opinions in Immunology 2008 20:709-716)), glomerulonephritis, chronic lant rejection, and rheumatoid arthritis.
In one aspect, the present invention es a compound of formula (I) or a ceutically acceptable salt thereof, for use in the treatment of an autoimmune condition, for example systemic lupus matosus (SLE), discoid (cutaneous) lupus, Sjorgens syndrome, Wegners granulomatosis and other vasculitides, bullous goid and pemphigus, idiopathic thrombocytopenic a (ITP), giant cell arteriosis, chronic idiopathic urticaria with and without auto-antibody status (chronic mune urticaria (New concepts in chronic urticaria, Current Opinions in Immunology 2008 -716)), glomerulonephritis, chronic transplant rejection, and rheumatoid arthritis. In one embodiment, the present ion provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the ent of an autoimmune condition which is chronic idiopathic urticaria with and without auto- antibody status. In another ment, the t invention provides a compound 40 of a (I) or a pharmaceutically acceptable salt thereof for use in the treatment of an autoimmune condition which is discoid (cutaneous) lupus.
In another aspect, the present invention es a method of treating an autoimmune condition, for example systemic lupus erythematosus (SLE), discoid (cutaneous) lupus, Sjorgens syndrome, Wegners granulomatosis and other itides, bullous pemphigoid and gus, idiopathic thrombocytopenic purpura (ITP), giant cell arteriosis, c idiopathic urticaria with and without auto- dy status, glomerulonephritis, c transplant rejection and rheumatoid arthritis, which method comprises administering to a subject, particularly a human subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In one ment, the t invention provides a method of treating an autoimmune disease which is c idiopathic ria with and without auto-antibody status, which method comprises administering to a subject, particularly a human subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention provides a method of treating an autoimmune disease which is discoid (cutaneous) lupus, which method comprises administering to a subject, particularly a human subjectin need thereof a therapeutically ive amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
In a further aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically able salt thereof, for the manufacture of a medicament for the treatment of an autoimmune ion, for example systemic lupus erythematosus (SLE), discoid (cutaneous) lupus, Sjorgens syndrome, Wegners granulomatosis and other vasculitides, bullous pemphigoid and pemphigus, idiopathic thrombocytopenic purpura (ITP), giant cell arteriosis, c thic urticaria with and without auto-antibody status, glomerulonephritis, chronic transplant rejection and toid arthritis. In one embodiment, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of an autoimmune ion which is chronic idiopathic ria with and without auto-antibody status. In another embodiment, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the cture of a medicament for the treatment of an mune condition which is discoid (cutaneous) lupus.
In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of an inflammatory disease which involves B cells.
In another aspect, the present invention provides a method of ng an inflammatory disease which involves B cells which method comprises stering to a subject, particularly a human subject in need thereof a therapeutically effective 40 amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
In a further aspect, the present invention provides the use of a compound of formula (I) or a ceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of an inflammatory disease which involves B cells.
Compounds of formula (I) are potentially of use in treating diseases resulting from opriate mast cell activation, for instance ic and inflammatory diseases particularly with skin manifestations.
In one aspect, the present ion provides a nd of formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease associated with inappropriate mast cell activation.
In another aspect, the present invention es a method of treating a disease associated with inappropriate mast cell activation which method comprises administering to a subject, particularly a human t in need thereof a therapeutically effective amount of a compound of formula (I) or a ceutically acceptable salt thereof.
In a further aspect, the t invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, for the cture of a medicament for the treatment of a disease associated with inappropriate mast cell tion.
In one , the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of an inflammatory disease and/or allergic disorder for example, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), , severe asthma, ulcerative colitis, Crohn’s disease, bronchitis, conjunctivitis, psoriasis, scleroderma, dermatitis, allergy, rhinitis, ous lupus, autoimmune bullous conditions including pemphigus and goid, mastocytosis and anaphylaxis.
In another aspect, the present invention provides a method of treating an inflammatory disease and/or allergic disorder for example, chronic ctive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), asthma, severe asthma, ulcerative colitis, Crohn’s disease, bronchitis, conjunctivitis, psoriasis, scleroderma, dermatitis, allergy, rhinitis, ous lupus, autoimmune bullous conditions including pemphigus and pemphigoid, mastocytosis and anaphylaxis, which method comprises stering to a subject, particularly a human subject in need thereof a eutically ive amount of a compound of formula (l)or a pharmaceutically able salt thereof.
In a further aspect, the present invention provides the use of a compound of formula 40 (I) or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of an inflammatory disease and/or allergic disorder for example, chronic ctive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), asthma, severe asthma, ulcerative colitis, Crohn’s disease, bronchitis, conjunctivitis, psoriasis, scleroderma, dermatitis, allergy, rhinitis, 2012/053948 cutaneous lupus, autoimmune bullous conditions including pemphigus and pemphigoid, mastocytosis and anaphylaxis.
Compounds of a (I) may also be used in combination with other classes of therapeutic , for example selected from anti-inflammatory agents, anticholinergic agents cularly an M1/M2/M3 receptor antagonist), [32- adrenoreceptor agonists, antiinfective agents such as antibiotics or antivirals, or antihistamines.
In another embodiment, compounds of formula (I) may be used in combination with other classes of therapeutic agents which are known in the art for treating autoimmune diseases, for instance e ing anti-rheumatic drugs including cyclosporine, methotrexate, sulphasalazine, prednisone, leflunomide, and quine/hydrochloroquine and also biopharmaceutical agents such as humanised monoclonal antibodies , for e including anti-TNF alpha blockers such as remicade, enbrel and humira, B cell depleting therapies such as rituximab and ofatumumab, and anti-Blys mabs such as belilumab.
The invention thus provides, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with one or more other therapeutically active agents, for e selected from an anti-inflammatory agent such as a osteroid or an NSAID, an anticholinergic agent, a [32-adrenoreceptor agonist, an antiinfective agent such as an antibiotic or an antiviral, an antihistamine, a disease modifying anti-rheumatic drug, and a biopharmaceutical agent such as humanised monoclonal antibodies (mabs), B cell depleting therapies and anti-Blys mabs. One embodiment of the invention encompasses combinations comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a Bg-adrenoreceptor agonist, and/or an anticholinergic, and/or a PDE-4 inhibitor, and/or an antihistamine, and/or a disease modifying anti-rheumatic drug, and/or a biopharmaceutical agent.
One embodiment of the invention encompasses combinations comprising one or two other therapeutically active agents.
It will be clear to a person skilled in the art that, where appropriate, the other therapeutic ingredient(s) may be used in the form of salts, for example as alkali metal or amine salts or as acid addition salts, or prodrugs, or as esters, for example lower alkyl esters, or as solvates, for e hydrates to optimise the activity and/or stability and/or al characteristics, such as solubility, of the therapeutic ient. It will be clear also that, where appropriate, the eutic ingredients 40 may be used in optically pure form.
Examples of [32-adrenoreceptor agonists include salmeterol (which may be a racemate or a single enantiomer such as the R—enantiomer), salbutamol (which may be a racemate or a single enantiomer such as the R—enantiomer), formoterol (which may be a racemate or a single diastereomer such as the R,R—diastereomer), salmefamol, fenoterol, carmoterol, etanterol, naminterol, clenbuterol, erol, terol, reproterol, bambuterol, indacaterol, terbutaline and salts thereof, for example the xinafoate (1-hydroxynaphthalenecarboxylate) salt of erol, the sulphate salt or free base of salbutamol or the fumarate salt of formoterol. In one embodiment the enoreceptor agonists are long-acting [32-adrenoreceptor agonists, for example, compounds which provide effective bronchodilation for about 12 hours or longer.
Other [32-adrenoreceptor agonists include those described in WOO2/066422, WOO2/070490, WOO2/076933, WOO3/024439, WOO3/072539, WOO3/091204, WOO4/016578, WOO4/022547, WOO4/037807, WOO4/037773, WOO4/037768, WOO4/039762, WOO4/039766, WOO1/42193 and WOO3/042160.
Examples of [32-adrenoreceptor agonists include: 3-(4-{[6—({(2R)—2-hydroxy[4-hydroxy(hydroxymethyl)phenyl]ethyl}amino) hexyl] oxy} butyl) esulfonamide; 3-(3-{[7-({(2R)—2-hydroxy[4-hydroxyhydroxymethyl) phenyl] ethyl}-amino) ] oxy} ) benzenesulfonamide; )—2-[(6—{2-[(2, 6-dichlorobenzyl) oxy] ethoxy} hexyl) amino]hydroxyethyl} (hydroxymethyl) phenol; 4-{(1R)—2-[(6-{4-[3-(cyclopentylsulfonyl)phenyl]butoxy}hexyl)amino]hydroxyethyl}- 2-(hydroxymethyl)phenol; N-[2-hydroxyl[(1R)—1-hydroxy[[2[[(2 R)—2-hyd roxy phenylethyl]amino]phenyl]ethyl]amino]ethyl]phenyl]formamide; N-2{2-[4-(3-phenylmethoxyphenyl)aminophenyl]ethyl}hydroxy(8-hydroxy— 2(1H)—quinolinonyl)ethylamine; and -[(R)—2-(2-{4-[4-(2-aminomethyl-propoxy)-phenylamino]-phenyl}-ethylamino)—1- hydroxy-ethyl]hydroxy-1H-quinolinone.
The Bg-adrenoreceptor agonist may be in the form of a salt formed with a pharmaceutically acceptable acid selected from sulphuric, hydrochloric, fumaric, ynaphthoic (for example 1- or 3-hydroxynaphthoic), cinnamic, substituted cinnamic, triphenylacetic, sulphamic, nilic, naphthaleneacrylic, benzoic, 4-methoxybenzoic, 2- or 4-hydroxybenzoic, 4-chlorobenzoic and 4-phenylbenzoic acid.
Examples of corticosteroids may include those described in WOO2/088167, 40 WOO2/100879, 2265, WOO2/12266, W005/005451, W005/005452, WOO6/072599 and WOO6/072600.
Anti-inflammatory corticosteroids are well known in the art. Representative examples include fluticasone propionate (e.g. see US patent 4,335,121), asone e (e.g. see US patent 7,101,866), beclomethasone 17-propionate ester, beclomethasone 17,21-dipropionate ester, dexamethasone or an ester thereof, mometasone or an ester thereof (e.g. mometasone furoate), ciclesonide, budesonide, flunisolide, methyl prednisolone, solone, thasone and 60c,9cx-difluoro-11B-hydroxy—16a—methyloxo-17a—(2,2,3,3- tetramethycyclopropylcarbonyl)oxy-androsta-1 ,4—diene—17B-carbothioic acid 8- cyanomethyl ester. Further examples of anti-inflammatory corticosteroids are described in W002/088167, W002/100879, W002/12265, W002/12266, W005/005451, W005/005452, WOO6/072599 and WOO6/072600.
Non-steroidal compounds having orticoid m that may possess selectivity for transrepression over transactivation and that may be useful in combination y include those covered in the following published patent ations and patents: WOO3/082827, W098/54159, WOO4/005229, WOO4/009017, WOO4/018429, WOO3/104195, WOO3/082787, WOO3/082280, WOO3/059899, WOO3/101932, W002/02565, WOO1/16128, WOOD/66590, 86294, WOO4/026248, WOO3/061651, WOO3/08277, WOO6/000401, WOO6/000398, WOO6/015870, WOO6/108699, WOW/000334 and W007/054294.
Examples of anti-inflammatory agents include non-steroidal anti-inflammatory drugs (NSAID’s).
Examples of NSAID’s e sodium cromoglycate, nedocromil sodium, phosphodiesterase (PDE) inhibitors (for example, theophylline, PDE4 inhibitors or mixed PDE3/PDE4 inhibitors), leukotriene antagonists, inhibitors of leukotriene synthesis (for example montelukast), iNOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine receptor agonists or antagonists (e.g. adenosine 2a agonists), cytokine antagonists (for example chemokine antagonists, such as a CCR3 nist) or inhibitors of cytokine synthesis, or 5- lipoxygenase tors. An iNOS (inducible nitric oxide synthase inhibitor) is preferably for oral administration. Examples of iNOS tors include those disclosed in W093/13055, W098/30537, W002/50021, W095/34534 and W099/62875. Examples of CCR3 inhibitors include those sed in W002/26722.
Examples of PDE4 inhibitors include ciscyano(3-cyclopentyloxy—4- methoxyphenyl)cyclohexancarboxylic acid, 2-carbomethoxycyano(3- cyclopropylmethoxy—4-difluoromethoxyphenyl)cyclohexanone and cis-[4-cyano 40 (3-cyclopropylmethoxy—4-difluoromethoxyphenyl)cyclohexanol]. Also, cyano- 4-[3-(cyclopentyloxy)methoxyphenyl]cyclohexanecarboxylic acid (also known as cilomilast) and its salts, esters, pro-drugs or physical forms (e.g. see U.S. patent ,552,438).
Other nds include AWD281 from Elbion (Hofgen, N. Lal. 15th EFMC Int Symp Med Chem (Sept 6—10, Edinburgh) 1998, Abst P.98; CAS nce No. 247584020-9); a 9-benzyladenine derivative nominated NCS-613 (INSERM); D-4418 from Chiroscience and Schering-Plough; a benzodiazepine PDE4 inhibitor identified as Cl-1018 (PD-168787) and attributed to Pfizer; a benzodioxole derivative disclosed by Kyowa Hakko in WO99/16766; K—34 from Kyowa Hakko; V—11294A from Napp (Landells, L.J. Lal. Eur Resp J [Annu Cong Eur Resp Soc (Sept 19-23, Geneva) 1998] 1998, 12 (Suppl. 28): Abst ; roflumilast (CAS reference No 162401 3) and a pthalazinone (e.g. see WO99/47505) from Byk-Gulden; Pumafentrine, (-)-p- [(4aR*,10bS*)—9-ethoxy—1,2,3,4,4a,10b-hexahydromethoxy methylbenzo[c][1,6]naphthyridin-6—yl]—N,N-diisopropylbenzamide which is a mixed PDE3/PDE4 inhibitor which has been prepared and published on by Byk-Gulden, now Altana; arofylline under development by Almirall-Prodesfarma; VM554/UM565 from Vernalis; or T-440 (Tanabe Seiyaku; Fuji, K. Lal. J col Exp Ther,1998, 284(1): 162), and T2585. r nds are disclosed in the published international patent application WOO4/024728 (Glaxo Group Ltd), WOO4/056823 (Glaxo Group Ltd) and 03998 (Glaxo Group Ltd).
Examples of anticholinergic agents are those compounds that act as antagonists at the muscarinic receptors, in particular those compounds which are antagonists of the M1 or M3 receptors, dual nists of the M1/M3 or M2/M3, receptors or pan- antagonists of the M1/M2/M3 receptors. Exemplary compounds for administration via inhalation include ipratropium (for example, as the bromide, CAS 222546, sold under the name Atrovent), oxitropium (for example, as the bromide, CAS 30286 0) and tiotropium (for example, as the bromide, CAS 1363105, sold under the name Spiriva). Also of interest are revatropate (for example, as the hydrobromide, CAS 262586—79-8) and LAS-34273 which is disclosed in 4118. Exemplary compounds for oral administration include pirenzepine (CAS 287977), darifenacin (CAS 1330994, or CAS 7 for the romide sold under the name Enablex), oxybutynin (CAS 56335, sold under the name Ditropan), terodiline (CAS 157935), odine (CAS 1249375, or CAS 1249376 for the tartrate, sold under the name Detrol), otilonium (for example, as the bromide, CAS 260950, sold under the name Spasmomen), trospium chloride (CAS 10405- 02-4) and solifenacin (CAS 2424781, or CAS 2424782 for the ate also known as YM-905 and sold under the name Vesicare).
Other anticholinergic agents include compounds which are disclosed in US patent 40 application 60/487981 including, for example: (3-endo)—3-(2,2-dithienylethenyl)-8,8-dimethylazoniabicyclo[3.2.1]octane bromide; (3-endo)—3-(2,2-diphenylethenyl)—8,8-dimethylazoniabicyclo[3.2.1]octane bromide; (3-endo)—3-(2,2—diphenylethenyl)—8,8—dimethyl-8—azoniabicyclo[3.2.1]octane 4- methylbenzenesulfonate; o)—8,8-dimethyl[2—phenyl-2—(2—thienyl)ethenyl]—8—azoniabicyclo[3.2.1]octane bromide; and (3-endo)—8,8-dimethyl[2—phenyl-2—(2—pyridinyl)ethenyl]—8— azoniabicyclo[3.2.1]octane e.
Further olinergic agents include compounds which are disclosed in US patent application 60/511009 including, for example: (endo)—3-(2—methoxy—2,2—di-thiophenyl-ethyl)—8,8—dimethyl-8—azonia- bicyclo[3.2.1]octane iodide; 3-((endo)—8—methyl-8—aza-bicyclo[3.2.1]octyl)—2,2—diphenyl-propionitrile; (endo)—8—methyl(2,2,2—triphenyl-ethyl)aza-bicyclo[3.2.1]octane; 3-((endo)—8—methyl-8—aza-bicyclo[3.2.1]octyl)—2,2—diphenyl-propionamide; 3-((endo)—8—methyl-8—aza-bicyclo[3.2.1]octyl)—2,2—diphenyl-propionic acid; (endo)—3-(2—cyano-2,2—diphenyl-ethyl)—8,8—dimethyl-8—azonia-bicyclo[3.2.1]octane iodide; (endo)—3-(2—cyano-2,2—diphenyl-ethyl)—8,8—dimethyl-8—azonia-bicyclo[3.2.1]octane bromide; 3-((endo)—8—methyl-8—aza-bicyclo[3.2.1]octyl)—2,2—diphenyl-propano|; N-benzyl((endo)—8—methyl-8—aza-bicyclo[3.2.1]octyl)—2,2—diphenyl-propionamide; (endo)—3-(2—carbamoyl-2,2—diphenyl-ethyl)—8,8—dimethyl-8—azonia-bicyclo[3.2.1]octane iodide; 1-benzyl[3-((endo)—8—methyl-8—aza-bicyclo[3.2.1]oct—3-yl)—2,2—diphenyl-propyl]— urea; 1-ethyl[3-((endo)—8—methyl-8—aza-bicyclo[3.2.1]octyl)—2,2—diphenyl-propyl]—urea; N-[3-((endo)—8—methyl-8—aza-bicyclo[3.2.1]octyl)—2,2—diphenyl-propyl]—acetamide; N-[3-((endo)—8—methyl-8—aza-bicyclo[3.2.1]octyl)—2,2—diphenyl-propyl]—benzamide; do)—8—methyl-8—aza-bicyclo[3.2.1]octyl)—2,2—di-thiophenyl-propionitrile; (endo)—3-(2—cyano-2,2—di-thiophen-2—yl-ethyl)—8,8—dimethyl-8—azoniabicyclo [3.2.1]octane iodide; N-[3-((endo)—8—methyl-8—aza-bicyclo[3.2.1]octyl)—2,2—diphenyl-propyl]— benzenesulfonamide; [3-((endo)—8—methyl-8—aza-bicyclo[3.2.1]oct—3-yl)—2,2—diphenyl-propyl]—urea; N-[3-((endo)—8—methyl-8—aza-bicyclo[3.2.1]octyl)—2,2—diphenyl-propyl]— methanesulfonamide; and (endo)—3-{2,2—diphenyl[(1-phenyl-methanoyl)—amino]—propyl}-8,8—dimethyl-8— azonia-bicyclo[3.2.1]octane bromide. 40 Further compounds include: (endo)—3-(2—methoxy—2,2—di-thiophenyl-ethyl)—8,8—dimethyl-8—azonia- bicyclo[3.2.1]octane iodide; (endo)—3-(2—cyano-2,2—diphenyl-ethyl)—8,8—dimethyl-8—azonia-bicyclo[3.2. 1 ]octane iodide; —3-(2—cyano-2,2-diphenyl-ethyl)-8,8—dimethylazonia-bicyclo[3.2.1]octane bromide; (endo)—3-(2—carbamoyl-2,2—diphenyl-ethyl)-8,8—dimethyl-8—azonia-bicyclo[3.2. 1 ]octane iodide; (endo)—3-(2—cyano-2,2-di-thiophenyl-ethyl)-8,8—dimethyl-8—azonia- bicyclo[3.2.1]octane iodide; and (endo)—3-{2,2—diphenyl[(1-phenyl-methanoyl)—amino]—propyl}-8,8—dimethyl-8— azonia-bicyclo[3.2.1]octane bromide.
In one embodiment the invention provides a combination comprising a compound of formula (I), or a pharmaceutically acceptable salt f, together with an H1 antagonist. Examples of H1 antagonists include, without limitation, methapyrilene, desloratadine, amelexanox, astemizole, azatadine, tine, acrivastine, brompheniramine, cetirizine, levocetirizine, efletirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, descarboethoxyloratadine, doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, yzine, fen, loratadine, levocabastine, mizolastine, mequitazine, mianserin, noberastine, meclizine, norastemizole, olopatadine, picumast, pyrilamine, hazine, terfenadine, tripelennamine, temelastine, trimeprazine and triprolidine, particularly cetirizine, levocetirizine, efletirizine and fexofenadine. In a further embodiment the invention es a combination comprising a nd of formula (I), or a pharmaceutically acceptable salt thereof, together with an H3 nist (and/or inverse agonist). Examples of H3 antagonists include, for example, those compounds disclosed in W02004/035556 and in W02006/045416. Other histamine receptor antagonists which may be used in combination with the nds of formula (I), or a pharmaceutically acceptable salt thereof, include antagonists (and/or e agonists) of the H4 receptor, for example, the compounds disclosed in Jablonowski et a/., J. Med. Chem. 46:3957-3960 (2003).
In one embodiment there is provided, a combination comprising a compound of a (I) or a pharmaceutically acceptable salt thereof together with a corticosteroid. In another embodiment there is provided, a combination sing a compound of a (I) or a pharmaceutically acceptable salt thereof together with an NSAID. In another embodiment there is provided, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an olinergic. In another embodiment there is provided, a combination comprising a compound of formula (I) or a pharmaceutically able salt thereof together with a Bg-adrenoreceptor agonist. In another embodiment there is provided, a combination comprising a compound of formula (I) or a pharmaceutically 40 able salt thereof together with an antiinfective. In another embodiment there is provided, a ation comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof er with an antihistamine. In another embodiment there is provided, a combination comprising a compound of a (I) or a pharmaceutically acceptable salt thereof together with a disease modifying anti- rheumatic drug. In a further embodiment there is provided, a combination sing a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a biopharmaceutical agent.
A nd of formula (I) will normally, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient. Accordingly, in another aspect the invention is directed to pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable rs, diluents or excipients.
The pharmaceutical compositions of compounds of formula (I) may be prepared and packaged in bulk form wherein a safe and effective amount of a compound of the formula (I) can be extracted and then given to the patient, such as with s or syrups. Alternatively, the pharmaceutical compositions of compounds of formula (I) may be prepared and packaged in unit dosage form wherein each physically discrete unit contains a safe and effective amount of a compound of the formula (I). The pharmaceutical compositions of compounds of formula (I) may also be prepared and packaged in a sub-unit dosage form wherein two or more sub-unit dosage forms provide the unit dosage form. When prepared in unit dosage form, the pharmaceutical compositions of compounds of formula (I) typically contain from about 0.1 to 99.9 wt.%, of the compound of formula (I), depending on the nature of the formulation.
In on, the ceutical compositions of compounds of formula (I) may optionally further comprise one or more additional therapeutically active compounds.
As used herein, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, ition or vehicle involved in giving form or consistency to the ceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled, such that interactions which would substantially reduce the efficacy of the nd of formula (I) when administered to a patient and would result in pharmaceutically unacceptable compositions are avoided. In addition, each excipient must of course be of sufficiently high purity to render it ceutically acceptable. itions sing a compound of formula (I), or a pharmaceutically acceptable salt thereof and one or more ceutically acceptable carriers, diluents or excipients will typically be provided as a dosage form adapted for administration to the patient by the desired route of stration. For example, 40 dosage forms e those adapted for: (1) oral administration, such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, ons, emulsions, sachets, and cachets; (2) topical dermal administration, such as , ointments, lotions, solutions, pastes, sprays, foams, and gels, (3) inhalation, such as aerosols and solutions; (4) intranasal administration, such as solutions or sprays; (5) parenteral administration, such as e solutions, suspensions, and powders for reconstitution and (6) intravitreal administration.
In one embodiment there is provided a dosage form d for topical dermal administration.
It will be appreciated that dosage forms adapted for oral administration are commonly used for treating autoimmune disease including rheumatoid arthritis and systemic lupus erythematosus, chronic idiopathic rias and heme malignancies. Dosage forms adapted for topical administration to the skin are commonly used for treating atopic dermatitis, psoriasis and chronic and acute urticaria conditions, and autoimmune s conditions including pemphigus and pemphigoid. Dosage forms adapted for inhalation or oral administration are commonly used for treating COPD; whilst dosage forms adapted for intranasal administration are commonly used for treating ic rhinitis.
Suitable pharmaceutically acceptable excipients will vary depending upon the particular dosage form chosen. In addition, le pharmaceutically acceptable excipients may be chosen for a particular function that they may serve in the composition. For example, certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically able excipients may be chosen for their ability to facilitate the production of stable dosage forms. Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the carrying or transporting the nd of formula (I) once stered to the patient from one organ, or portion of the body, to another organ, or portion of the body. Certain pharmaceutically acceptable excipients may be chosen for their ability to enhance patient compliance.
Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, ts, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweetners, flavouring agents, flavour masking agents, ing , anticaking agents, humectants, chelating agents, plasticizers, viscosity increasing , antioxidants, preservatives, stabilizers, surfactants, and buffering agents.
The skilled artisan will appreciate that certain pharmaceutically acceptable excipients may serve more than one function and may serve alternative functions ing on how much of the excipient is present in the formulation and what other ingredients are present in the formulation. 40 d ns possess the knowledge and skill in the art to enable them to select suitable pharmaceutically acceptable excipients in riate amounts for use in the invention. In addition, there are a number of resources that are available to the skilled artisan which describe pharmaceutically able excipients and may be useful in selecting le pharmaceutically acceptable excipients. Examples include ton's Pharmaceutical Sciences (Mack hing Company), Remington: The Science and Practice of Pharmacy, (Lippincott Williams & s), The Handbook of Pharmaceutical Additives (Gower Publishing d), and The Handbook of Pharmaceutical Excipients (the American ceutical Association and the Pharmaceutical Press).
The ceutical itions of compounds of formula (I) are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's ceutical Sciences (Mack Publishing Company).
Oral solid dosage forms such as tablets will typically comprise one or more pharmaceutically acceptable excipients, which may for example help impart satisfactory processing and compression characteristics, or e additional desirable physical teristics to the tablet. Such pharmaceutically acceptable excipients may be selected from diluents, binders, glidants, lubricants, disintegrants, colorants, flavourants, sweetening agents, rs, waxes or other solubility- modulating materials.
Dosage forms for topical administration to the skin may, for example, be in the form of ointments, creams, s, eye ointments, eye drops, ear drops, impregnated dressings, and aerosols, and may contain appropriate conventional additives, including, for e, preservatives, solvents to assist drug penetration, and emollients in ointments and creams. Such topical ations may also contain compatible conventional carriers, for example cream or ointment bases, and ethanol or oleyl alcohol for lotions. Such carriers may constitute from about 1% to about 98% by weight of the formulation; more usually they will constitute up to about 80% by weight of the formulation.
Dosage forms for parenteral administration will generally comprise fluids, particularly intravenous fluids, i.e., sterile solutions of simple chemicals such as sugars, amino acids or electrolytes, which can be easily carried by the atory system and assimilated. Such fluids are typically prepared with water for injection USP. Fluids used commonly for intravenous (IV) use are disclosed in Remington, The Science and Practice of Pharmacy [ibid]. The pH of such IV fluids may vary, and will typically be from 3.5 to 8, as known in the art.
Dosage forms for nasal or inhaled administration may conveniently be formulated as aerosols, solutions, drops, gels or dry powders.
Dosage forms for topical administration to the nasal cavity (nasal administration) include pressurised aerosol formulations and aqueous formulations administered to the nose by pressurised pump. Formulations which are essurised and adapted for nasal administration are of particular interest. Suitable formulations contain water as the diluent or r for this purpose. Aqueous formulations for stration to the nose may be provided with conventional excipients such as buffering agents, ty modifying agents and the like. Aqueous formulations may also be administered to the nose by nebulisation.
Dosage forms for nasal administration are provided in a metered dose device. The dosage form may be provided as a fluid formulation for delivery from a fluid dispenser having a dispensing nozzle or dispensing orifice h which a metered dose of the fluid formulation is dispensed upon the application of a user-applied force to a pump mechanism of the fluid dispenser. Such fluid dispensers are generally provided with a reservoir of multiple metered doses of the fluid formulation, the doses being dispensable upon sequential pump actuations. The dispensing nozzle or orifice may be configured for insertion into the ls of the user for spray dispensing of the fluid formulation into the nasal cavity. In one embodiment, the fluid dispenser is of the general type described and illustrated in W02005/044354A1. The dispenser has a housing which houses a fluid discharge device having a compression pump mounted on a container for containing a fluid formulation. The housing has at least one finger- operable side lever which is movable inwardly with respect to the housing to cam the container upwardly in the housing to cause the pump to compress and pump a metered dose of the formulation out of a pump stem through a nasal nozzle of the housing. A particularly preferred fluid dispenser is of the general type illustrated in Figures 30-40 of /044354A1.
Aerosol compositions, e.g. for inhaled administration, can comprise a solution or fine suspension of the active substance in a pharmaceutically acceptable aqueous or non-aqueous solvent. Aerosol formulations can be ted in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device or inhaler. Alternatively the sealed container may be a unitary dispensing device such as a single dose nasal r or an aerosol dispenser fitted with a metering valve (metered dose inhaler) which is intended for disposal once the contents of the ner have been exhausted.
Where the dosage form comprises an aerosol dispenser, it preferably contains a suitable lant under pressure such as compressed air, carbon dioxide or an c propellant such as a hydrofluorocarbon (HFC). Suitable HFC propellants include 1,1,1,2,3,3,3-heptafluoropropane and 1,1,1,2—tetrafluoroethane. The aerosol dosage forms can also take the form of a tomiser. The pressurised l may contain a solution or a suspension of the active compound. This may require the oration of additional excipients e.g. co-solvents and/or surfactants to improve 40 the dispersion characteristics and homogeneity of suspension formulations. Solution ations may also require the addition of co-solvents such as ethanol. Other excipient modifiers may also be incorporated to improve, for e, the stability and/or taste and/or fine particle mass characteristics t and/or profile) of the formulation.
For pharmaceutical compositions suitable and/or adapted for inhaled administration, it is preferred that the ceutical ition is a dry powder inhalable composition. Such a composition can comprise a powder base such as lactose, glucose, trehalose, mannitol or starch, a compound of formula (I) (preferably in particle-size-reduced form, e.g. in micronised form), and optionally a performance modifier such as L-leucine or another amino acid, cellobiose octaacetate and/or metals salts of stearic acid such as magnesium or calcium stearate. Preferably, the dry powder inhalable ition comprises a dry powder blend of lactose and a compound of formula (I). The lactose is preferably lactose hydrate e.g. lactose drate and/or is preferably inhalation-grade and/or fine-grade lactose.
Preferably, the particle size of the e is defined by 90% or more (by weight or by volume) of the lactose particles being less than 1000 microns (micrometres) (e.g. -1000 microns e.g. 30-1000 microns) in diameter, and/or 50% or more of the lactose les being less than 500 microns (e.g. 10-500 s) in diameter. More preferably, the particle size of the lactose is defined by 90% or more of the lactose particles being less than 300 s (e.g. 10-300 s e.g. 50-300 microns) in diameter, and/or 50% or more of the lactose particles being less than 100 microns in diameter. Optionally, the particle size of the lactose is defined by 90% or more of the lactose particles being less than 100-200 microns in diameter, and/or 50% or more of the lactose particles being less than 40-70 microns in diameter. Most importantly, it is preferable that about 3 to about 30% (e.g. about 10%) (by weight or by volume) of the particles are less than 50 s or less than 20 s in diameter. For example, without limitation, a suitable inhalation-grade lactose is E9334 lactose (10% fines) (Borculo Domo ients, Hanzeplein 25, 8017 JD Zwolle, Netherlands).
Optionally, in particular for dry powder inhalable compositions, a pharmaceutical composition for d administration can be orated into a plurality of sealed dose containers (e.g. ning the dry powder composition) mounted longitudinally in a strip or ribbon inside a suitable inhalation device. The ner is rupturable or peel-openable on demand and the dose of e.g. the dry powder composition can be administered by inhalation via the device such as the DISKUS® device, marketed by mithKline. The DISKUS® inhalation device is for example described in GB 2242134 A, and in such a device at least one container for the pharmaceutical composition in powder form (the container or containers preferably being a plurality of sealed dose containers mounted longitudinally in a strip or ribbon) is d between two members peelably secured to one another; the device comprises: a means of defining an opening station for the said container or containers; a means for peeling the members apart at the opening station to open the ner; and an 40 outlet, communicating with the opened container, through which a user can inhale the pharmaceutical composition in powder form from the opened container.
A composition of invention compound of formula (I), for intranasal administration, may also be adapted for dosing by insufflation, as a dry powder formulation.
For dosage forms for d administration, where the compound of formula (I) is present as a dry powder or in suspension, then it is preferred that it is in a particle- size-reduced form. ably the size-reduced form is obtained or obtainable by micronisation. The able particle size of the size-reduced (e.g. micronised) compound or salt is defined by a D50 value of about 0.5 to about 10 microns (for example as measured using laser diffraction).
It will be appreciated that when the compounds of formula (I) are administered in combination with other therapeutic agents normally administered by the inhaled, intravenous, oral, topical or intranasal route, that the resultant pharmaceutical composition may be administered by the same routes.
The composition may contain from 0.1% to 100% by weight, for example from 10 to 60% by weight, of the active material, depending on the method of administration.
The composition may contain from 0% to 99% by weight, for example 40% to 90% by weight, of the carrier, ing on the method of administration.The compounds of the formula (I) may iently be administered in amounts of, for example, 1ug to 2g. The precise dose will of course depend on the age and condition of the patient and the particular route of administration .
Biological test methods Compounds may be tested for in vitro activity in accordance with the following assays: 1. Basic SYK enzyme activity 3ul of SYK lysate diluted 16-fold in assay buffer (20mM TRIS pH 7.4, 0.01% BSA,0.1% Pluronic F-68) was added to wells ning 0.1ul of various concentrations of compound or DMSO vehicle (1.7% final) in a Greiner low volume 384 well black plate. Following 15 minutes pre-incubation at room temperature, the reaction was initiated by the addition of 3ul of substrate reagent ning Y7 Sox peptide, (lnvitrogen Cat. # KNZ3071, 5uM final), ATP (35uM final) and MgClg (10mM final) in assay . The reaction was ted at room temperature before measuring fluorescence intensity (Aex 360Mem 485) on an on plate reader (Perkin Elmer Life Sciences, Waltham, MA, USA) at 15 s and 55 minutes post- substrate addition. 40 The compounds of the Examples were tested essentially as described above, and were found to have a plC50 of 5.5 to 7.5. The compounds of Examples 1 to 8 were tested essentially as described above and were found to have an average plC50 value in this assay of 2 6.0. The compound of Example 2 was tested essentially as described above and was found to have a plC50 of 7.1.
Those of skill in the art will recognize that in vitro binding assays and cell-based assays for functional activity are subject to variability. Accordingly, it is to be understood that the values for the plC50s d above are exemplary only.
Preparation of SYK lysate i. Preparation of Ramos cell lysates Ramos B Cells (human B cells of Burkitt’s lymphoma, clone 296.4C10, ATCC) were cultured in suspension in growth medium (RPMl-1640, Sigma; supplemented with 2mM L-glutamine, Gibco; 10mM Hepes, Sigma; 1mM sodium pyruvate, Sigma; 10% v/v heat-inactivated FCS, Gibco). Cells were grown in Corning Cellstacks (6360 cm2) in 1 litre volume and viability and cell density were monitored daily. Cells were maintained at <1.5 x 10e6/ml and >92% viability Large scale production runs were generated from Large Scale Intermediate Aliquots (LSlA’s) of frozen Ramos cells as this was found to give greater reproducibility than tion from a continuously growing culture of Ramos cells.
The large scale production run cells were generated in four steps: 1. Thaw LSlA into 1 x Cellstack; 2. Expand e into 4 x ack; 3. Expand from 4 to 12 x Cellstacks; 4. Harvest all 12 Cellstacks Cellstacks were harvested in 2L centrifuge bottles using a Sorvall Mistral centrifuge, 2000rpm, 10 minutes, 4°C. (2L x 2x106 cells/ml = 4 x 109 cells total) (Notes for cell scale-up: If the cell density exceeded 1.8 x 10e6/ml or ity dropped below 90% the Syk prep obtained post-stimulation was likely to be of lower activity).
Also, repeated passage of the Ramos cells seemed to have a detrimental effect on Syk ty when cell growth is done at scale (this did not seem to be the case in small scale cultures) — it is recommended always to use LSlA’s and modular scale-up for large scale preps. ii. Stimulation of Ramos Cells with anti-lgM Ab to e Syk & Preparation of lysates Cells were ated at 20x106 cells/ml using 15ug/ml (final concentration) anti-lgM antibody. Following harvest (as described above), a total of 4 x 109 cells were 40 resuspended in 180mls pre-warmed (37°C) DPBS in a Corning 500ml fuge bottle. 20mls anti-lgM antibody at ml were added to each 500ml centrifuge bottle. (working stock made up in DPBS pre-warmed to 37°C). Cells were ted for exactly 5 minutes at 37°C following the addition of anti lgM antibody. Following 5 minutes stimulation, 300mls ice-cold DPBS were added to each bottle to stop the WO 23311 stimulation ( temperature drops to ~12 deg C) then cells were centrifuged at 2000rpm (Sorvall Legend RT+ centrifuge - pre-chilled to 4 deg C). Cells were washed by resuspension in ice-cold DPBS and centrifugation as above. The cell pellet was then lysed in ice-cold lysis buffer ning 1% triton-x-100 at a ratio of 150u|/1x 107 cells (i.e. 48mls lysis buffer). Following the on of lysis buffer, the cells were pipetted up & down & kept on ice for 15 minutes. The clarified lysate was then obtained by centrifugation ll Evolution RC (SLA-1500 rotor, ~20,000g (~14,500rpm), 45min, 4°C).
Lysate was aliquoted, snap-frozen on dry-ice & stored at -80°C prior to assay.
Materials Ramos Cells: Human B cells of ts lymphoma, clone 296.4C10 (ATCC).
Growth Media: 500ml RPMl, 10% heat inactivated FCS, 2mM L-Glutamine, 2mM HEPES, 1mM sodium te.
RPMl: Sigma R0883, stores CT5652 Foetal Calf Serum: Gibco 10099-141, stores CT2509 L-Glutamine: 200mM, Gibco 25030, stores CT3005 HEPES: 1M, Sigma H0887, stores CT5637 Sodium Pyruvate: 100mM, Sigma S8636, stores CT7741 gM Ab: Goat anti-human lgM ((Fab’)2 fragments) in PBS. lnvitrogen, custom- made preparation (azide free and low endotoxin levels). Catalogue no. NON0687, Lot 1411913. 2.74mg/ml.
D-PBS: Dulbeccos phosphate buffered saline, Sigma D8537 Lysis Buffer: 50mM TRIS pH7.5 + 150mM NaCl + 1% Triton-X-100 + 2mM EGTA + 1:100 dilution inhibitor cocktails (Phosphatase inhibitor cocktail set ll, Calbiochem cat no. 524625 & se inhibitor cocktail set V, Calbiochem cat no. 539137) Triton-X-100: Roche 10 789 704 001 (GI 198233X, SC/159824). Made up as a 20% stock in water.
EGTA: Sigma E4378. Added solid directly to buffer. 2. B cell activity assays 2.1. Ramos pErk assay Principle of the assay Ramos B cells (human B cells of Burkitt’s Lymphoma) are stimulated using gM.
This results in the recruitment of SYK to the B cell receptor. The subsequent autophosphorylation of Syk leads to initiation of a signalling cascade resulting in B 40 cell activation via the Erk MAP Kinase pathway. As a result Erk is phosphorylated and following cell lysis is ed by an immune capture assay.
Stimulation of Ramos cells with anti-lgM Cells were plated at a density of 2.5x105/well in a volume of 25u| assay medium (RPMI containing 10% heat inactivated foetal calf serum, 1% amine) in 96 v- well polypropylene plates. 25u| appropriately diluted compound solution was added and the plate incubated for 30min at 37°C with 5% C02. Cells were stimulated with 5ul Fab’g fragments of goat anti-human lgM (5ug/ml final) for 7min at 37°C. Cells are lysed by the addition of 55uL 2x RIPA lysis buffer for 2h at 4°C. Lysate may be frozen at this point at -80°C. pErk MSD assay 50u| cell lysate was transferred to a 96 well MSD plate coated with anti-pErk1/2 (Thr/Tyr: 4; 185/187) capture antibody and incubated for 16 hours at 4°C or 3 hours at room temperature. The plate was washed and an anti-pErk ion antibody added (25pl/well) for 1 hour at room temperature. This was removed, 150uL MSD read buffer added and the resultant electrochemiluminescence signal measured.
Compound Preparation Compound was prepared as a 10mM stock in DMSO and a dilution series prepared in DMSO using 9 successive 5-fold dilutions. This dilution series was diluted a further 1:100 with assay medium to give the final concentration range to be tested of 5x10'5 to 2.56x10'11M. Compound ons were prepared using the Biomek 2000 and Biomek Nx automated robotic pipetting systems.
Compounds of Examples 1-4, 6, 7, 9, 10-12, 15-17, 19, 20, 22, 24, 26-39, 41, 45, 46, 48 and 49 were tested ially as described above, and were found to have average plC50 values of 5.2 to 6.8. The compounds of Examples 1, 2, 3 and 4 were tested essentially as described above and were found to have an average plC50 value in this assay of 2 6.0.
Those of skill in the art will recognize that in vitro binding assays and cell-based assays for functional activity are subject to variability. ingly, it is to be understood that the values for the plC50s recited above are exemplary only.
Intermediates and Examples General All temperatures are in °C.
BOC refers to tert—butoxycarbonyl BOCgO refers to t—butyl dicarbonate BuOH refers to butanol 40 ngCOg refers to caesium carbonate DCM / CH2CI2 refers to dichloromethane DEAD refers to diethyl azodicarboxylate Dioxane refers to 1,4-dioxane DIPEA refers to N, N-diisopropylethylamine DMSO refers to dimethylsulfoxide DME refers to 1, 2—dimethoxyethane DMF refers to N,N-dimethylformamide Dppf refers to 1,1 ’-Bis(diphenylphosphino)ferrocene EA refers to ethyl acetate EDC refers to N-(3-Dimethylaminopropyl)-N’-ethylcarbodiimide Et3N refers to triethylamine Ether refers to diethyl ether EA/ EtOAc refers to ethyl acetate h refers to hours HCI refers to hydrogen chloride HOBT refers to 1-hydroxybenzotriazole HPLC refers to high performance liquid chromatography K2C03 refers to potassium carbonate KOH refers to potassium hydroxide LCMS refers to liquid chromatography— mass spectroscopy MDAP refers to mass directed automated preparative chromatography min refers to minutes NaHC03 refers to sodium bicarbonate NH4C| refers to um chloride NMP refers to N-methylpyrrolidone PEPPSI refers to Pyridine-Enhanced alyst Preparation Stabilization and lnitiation Pd/C refers to palladium on carbon PdCI2.dppf refers to [1, 1’- bis(diphenylphosphino)ferrocene] dichloropalladium Pd(PPh3)4 or Tetrakis refers to is (triphenylphosphine) palladium (0) Pinacol ne refers to 4,4,4',4',5,5,5',5'—octamethyl-2,2'-bi-1,3,2—dioxaborolane r.t. refers to room temperature Rt refers to retention time SiOz refers to silicon dioxide TEA refers to triethylamine Tf refers to trifluoromethanesulfonyl TFA refers to trifluoroacetic acid THF refers to tetrahydrofu ran c refers to thin layer chromatography 1H NMR spectra were recorded using a Bruker DPX 400MHz, referenced to 40 tetramethylsilane.
Mass a were recorded on a SHIMADZU LCMS 2010 EV Spectrometer using ve / negative electrospray. Sample preparation was done in 100 % methanol and the samples were injected via direct injection port Silica chromatography techniques include either automated (Flashmaster, Biotage SP4) techniques or manual chromatography on pre-packed cartridges (SPE) or manually-packed flash columns.
When the name of a commercial supplier is given after the name of a compound or a reagent, for instance “compound X (Aldrich)” or “compound X / Aldrich”, this means that compound X is obtainable from a commercial supplier, such as the commercial er named.
Similarly, when a literature or a patent reference is given after the name of a compound, for instance compound Y (EP 0 123 456), this means that the compound may be prepared as bed in the named reference.
The names of the above mentioned Examples have been obtained using the compound naming programme “ACD Name Pro 6.02”.
General HPLC method: HPLC was carried out using X-Bridge C18 250 X 4.6 mm, 5 micron at 267 nm.
Column flow was 1 mL /min and solvents used were 0.1% TFA in water HPLC grade (A) and 0.1% TFA in MeCN Gradient grade (B), with an injection volume of 10 uL.
Sample preparation in 250 ppm in Water: MeCN.
Method is as described below. l LC-MS methods: Method-A LC-MS was d out using X-bridge C18 150 X 4.6 mm, 5 micron column. The UV detection was done at wavelength of maximum absorption oned on individual spectra). The mass a were recorded on a ZU LCMS 2010EV Spectrometer using Positive / negative electro spray. Column flow was 1 mL /min and solvents used were 0.1 % formic acid in HPLC grade water (A) and 0.1 % formic acid in MeCN HPLC grade (B), with an injection volume of 10 uL. Sample preparation was at 250 ppm in MeCN + water.
Method is as described below.
Method-B LC-MS was carried out using X-bridge C18 150 X 4.6 mm, 5 micron column. The UV detection was done at wavelength of maximum absorption (mentioned on individual spectra). The mass spectra were recorded on a SHIMADZU LCMS 2010 EV Spectrometer using Positive / ve electro spray. Column flow was 1 mL /min and solvents used were 0.05 % Ammonium Acetate in HPLC grade water (A) and 0.05 % Ammonium e in Methanol HPLC grade (B), with an injection volume of 10 uL. Sample preparation was at 250 ppm in MeOH + water.
Method is as described below. 0.01 Method C LC/MS (Aglient) was conducted on a HALO C18 column (50mm x 4.6mm i.d. 2.7um packing diameter) at 40 degrees centigrade, eluting with 0.1% v/v solution of Formic Acid in Water (Solvent A) and 0.1% v/v solution of Formic Acid in Acetonitrile (Solvent B) using the following elution gradient 0-1min 5% B, 1-2.01min 95% B, 2.01 — 2.5min 5% B at a flow rate of 1.8ml/min. The UV ion was a summed signal at wavelength: 214nm and 254nm. MS: lon Source: ESI; Drying Gas Flow: 10 L/min; Nebulizer Pressure: 45psi; Drying Gas Temperature: 330 0C; Capillary Volvage: 4000V.
Preparative HPLC method used for the purification of compound Example 5: Preparative HPLC was carried out on Waters Delta 600 using Gemini C18 150 X 21.2 mm, 5 micron column with the UV detection at 251 nm on a UV detector.
Column flow was 21 mL /min. and solvents used were 0.1% TFA in water HPLC grade (A) and 0.1% TFA in itrile HPLC grade (B). Sample was ed in 1:1 Water & Acetonitrile.
Method is as described below. ative HPLC method used for the purification of compound Example 6: Preparative HPLC was carried out using ACE C18 250 X 21.2 mm, 5 micron column with the UV detection at 249 nm on a PDA detector. Column flow was 21 mL /min. and solvents used were 0.1% TFA in water HPLC grade (A) and 0.1% TFA in MeCN Gradient grade (B). Sample was prepared in a mixture of water and itrile.
Method is as described below. 0.01 Other nds purified by preparative HPLC were purified by methods similar to those described above for examples 5 and 6 Intermediate 1: 1 1-dimeth leth l 7- 4 4 5 5-tetrameth M 3 2-dioxaborolan l - 12 4 5-tetrah dro-3H—3-benzaze inecarbox late To a degassed mixture of 1,1-dimethylethyl 7-{[(trifluoromethyl)sulfonyl]oxy}-1,2,4,5— tetrahydro-3H—3-benzazepinecarboxylate (9.9g) (which can be prepared according to J. Med Chem. 2007, 50(21) 5076-5089), 4,4,4',4',5,5,5',5'-octamethy|-2,2'—bi-1,3,2— orolane , potassium acetate (7.3g) and dppf (0.833g) in dioxane (165ml) was added PdClgdppf.CH2C|2 (1.2g). The reaction mixture was again degassed with nitrogen/vacuum cycles. This was heated at 100°C for 18h. It was diluted with ethyl acetate and ed through celite. The filtrate was concentrated to yield a crude product. This was purified by column chromatography eluting with a 0-6% gradient of ethyl acetate in hexane to give the title compound as a white solid (6.2g) LCMS (Method B): Rt = 8.00 min, [MH]+-100= 274 (loss of ECG group as artefact of the mass oscopy conditions) Intermediate 18I 2-bromomethylpyridinol To a solution of 5-hydroxymethlypyridine (Commercial, Aldrich, 44.5g) in pyridine (400ml) is added dropwise over 30 min at room temperature a solution of bromine (71.64g) in pyridine (550ml). The reaction mixture was d for an additional 1.5h.
The reaction mixture was poured into water (4 litres), stirred for a few minutes and extracted with diethyl ether (4 X 300ml). The combined organics were dried over sodium sulphate and concentrated in vacuo to give a brown solid that was purified through silica using a 0-30% ethyl acetate in hexane system, to give the title compound as a beige solid, 37g.
NMR 1H NMR (400 MHz, DMSO-d6) 5ppm 10.43 (1H, s, OH), 7.16 ppm (1H, d, CH), 7.06 (1H, d, CH), 2.31 (3H, s, CH3) Intermediate 19 4-eth l ridin lmethanol / OH A solution of 4-ethylpyridine (Commercial, e.g. Sigma-Aldrich) (10.7g), um peroxydisulfate (45.6g) and trated sulphuric acid (4.5ml) in methanol (150m|)/ water (70ml) was refluxed for 24h. The reaction e was slowly added onto aqueous sodium bicarbonate and extracted with form (4 X 500ml). This was dried over sodium sulphate, concentrated in vacuo and purified through silica using 0-60% ethyl e in hexane to give the title compound, 1.16g Mass Spec: [MH]+ = 138.0 Intermediate 20 2-bromoeth lox henol To a solution of 4-(ethyloxy)phenol (Commercial eg Aldrich) (1.0g) in chloroform (5ml) cooled to 0°C was added bromine (1.26g) dropwise over 20min. The resulting mixture was stirred at 25C for 2h, before washing tially with aqueous sodium bicarbonate, and brine. The cs were dried over sodium sulphate, filtered and concentrated in vacuo to yield the title compound, 1.8g LCMS (Method A): Rt = 6.52 min, [MH]+= 215, 217 Intermediate 65I ohydroxy-N—methylbenzamide To a stirred solution of 3-bromo—4-hydroxybenzoic acid (Commercial eg Aldrich) (2.0g), EDC (2.65g), HOBT (1.41g) and TEA (6.2ml) in DCM (60ml) was added methylamine hydrochloride (1.87g). This was stirred at 25-300 for 16h. The solvent was removed under reduced re. The residue was dissolved in water and ted with ethyl acetate. The organics were dried (sodium sulphate) and concentrated in vacuo to yield the title compound, 0.57g LCMS (Method B): Rt = 4.76 min Prepared similarly using a different amine was intermediate 66. sation 3-bromo—4-h6ydroxy- Dimethylamine, LCMS hydrochloride (Method B): N,N- = 5.21 dimethylbenzamide min, [MH]+= 244, 266 Intermediate 67I 3-bromohydroxybenzamide To a stirred solution of 3-bromo—4-hydroxybenzoic acid (0.5g) and DMF (0.1ml) in DCM (10ml) was added dropwise oxalyl de (0.6ml). After stirring for 2h, ammonia gas was purged h. After completion of reaction by tlc, the solvent was removed under reduced pressure. The residue was dissolved in water and extracted with ethyl acetate. The organics were dried over sodium sulphate and concentrated in vacuo to yield the title compound, 0.18g LCMS (Method A): Rt = 4.33 min, [MH]+= 216, 218 lntermediate6812-bis meth lox meth lox meth lox benzene /OVO\©:O\0/ To a stirred solution of 3,4-bis(methyloxy)phenol (Commercial eg Alfa Aesar) (1.0g) and DIPEA (2.28mi) in DCM (15ml) was added chloromethyl methyl ether (0.74mi) at 0C. After stirring at 25-30C for 17h, the reaction was washed with dilute hydrochloric acid and ted aqueous sodium onate. This was dried over sodium sulphate and purified through silica eluting with 0-5% ethyl acetate in hexane, to give the title compound, 0.80g LCMS d A): Rt = 5.99 min, [MH]+= 199 Intermediate 69 2-bromo-3 4-bis meth lox meethyloxflmethyl |oxytbenzene /\/ \ To a stirred solution of s(methyloxy)—4-{[(methyloxy)methyl]oxy}benzene (4.0g) and TMEDA (3.93 ml) in dry diethyl ether (50ml) was added tert-butyllithium (1.7M in pentane, 23.76 ml) at -70C. The reaction was stirred at this temperature for 1h before adding bromine (0.15mi). This was allowed to stir at 0C for 3h. The reaction was quenched by on of 20% aqueous sodium dithionite and extracted with ethyl acetate. The organics were washed with dilute hydrochloric acid, aqueous sodium bicarbonate, brine and dried over sodium sulphate to yield a crude product. This was purified through silica, eluting with 0-10% ethyl acetate in hexane to give the title compound, 1.4g Mass Spec: [MH]+= 277, 279 Intermediate 70 o-3 4-bis meth lox henol HO O\ To a stirred solution of 2-bromo-3,4-bis(methyloxy)—1- {[(methyloxy)methyl]oxy}benzenein ol (10ml) was added hydrochloric acid (12M, 0.12mi) at 250. The reaction mixture was stirred at 400 for 5h. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organics were washed with brine, dried over sodium sulphate and concentrated in vacuo. The crude product was purified h silica eluting with 0- 4% ethyl acetate in hexane, to give the title compound, 0.65g LCMS (Method B): Rt = 5.58 min, [MH]+= 233 Intermediate 2: 2-bromo 4-meth l ridin lmeth lox ridine \ Br / O N \N A mixture of 2-bromopyridinol (commercially available, e.g. from Aldrich) (2.9g) and potassium ate (6.94g) in DMF (25ml) was stirred for 20min before adding 2-(chloromethyl)methy|pyridine hydrochloride (for preparation see WO 2008/141011) (3g). This was d at room temperature overnight. The on mixture was poured into ice/water and the solid formed was ted by filtration, washed with hexane and dried to give the title compound, 2.87g (61%).
LCMS (Method A): Rt = 4.27 min, [MH]+ = 279,281.
The following intermediates were similarly prepared: a . ent sation 3 2- Br 1.99 LCMS 2-({[2-bromo (chloromethyl)- (39%) (Method A): (methyloxy)phenyl]0xy} 4- = 5.16 methyl)—4- methylpyridine, min, [MH]+= methylpyridine hloride 308, 310 Preparation: J. Organic Chem. 2003, 68 (4) 1401- 1408 4 2- Br 3g (59%) LCMS 2-({[2-bromo (chloromethyl)- HO- : (Method A): (methyloxy)phenyl]0xy} 4- = 5.71 )—4- methylpyridine, min, [MH]+= methylpyridine hydrochloride 308, 310 Preparation: Synthetic Communications, 2007, 37 2- 2.6g LCMS 1-(3-bromo—4-{[(4- (chloromethyl)- (49%) (Method A): methyl 4- = 5.29 pyridinyl)methyl]oxy}ph methylpyridine, min, [MH]+= enyl)ethanone hydrochloride 320, 322 Preparation: 6 2- 1.3g LCMS 2-{[(2-bromo (chloromethyl)- (81%) (Method B): fluorophenyl)oxy]methy 4- = 7.39 ethylpyridine methylpyridine, min, [MH]+= hydrochloride 296, 298 7 2- *3.1g LCMS romo—4-[(2- (chloromethyl) (35%) (Method B): pyrazinylmethyl)oxy]ph pyrazine = 5.29 enyl}ethanone (Preparation min, [MH]+= WC 2010/ 307, 309 132615 Preparation: 2010/102154 2— Br 3.09 LCMS 2-{[(2- (chloromethyl)— HQ *(99%) (Method A): bromophenyl)oxy]meth 4- = 4.53 yl} (methyloxy)pyr min, [MH]+= loxy)pyridine idine, 294, 296 CommerCIal eg AldrIch_ _ hydrochloride Commercial eg ABCR GmbH 9 2- Br #1169 HPLC: Rt = 1-{3-bromo[(2- (Bromomethyl) HQ (74%) 10.31 min. pyridinylmethyl)oxy]phe pyridine Mass Spec: nyl}ethanone hydrobromide [MH]+= Commercial 305.9 (Aldrich) 0 Preparation: 21 2- Mass Spec: 2-bromo(1,1- (chloromethyl)— [MH]+= ylethyl)—3-{[(4- 4- 334.9 methyl methylpyridine, pyridinyl)methyl]oxy}py hydrochloride ridine Preparation: ediate 22 2- LCMS 2-({[2-bromo (Bromomethyl) (Method A): (methyloxy)phenyl]oxy} pyridine = 7.86 methyl)pyridine hydrobromide min. [MH]+= Commercial 294, 296 (Aldrich) 23 2- HPLC: Rt -bromomethyl- omethyl) 8.66 min. 3- pyrazine pyridinyl)oxy]methyl}py razine Preparation:_ lntermedIate_ 24 2- HPLC: Rt 2-({[2-bromo (chloromethyl) 9.54 min. (methyloxy)phenyl]oxy} pyrazine methyl)pyrazine Commercial e Apollo 2- Br 11.39 Mass Spec: 2-bromo—6-methyI (chloromethyl)— HQ [MH]+= {[(4-methyI 4- \N | 292.9, 295 pyridinyl)methyl]oxy}py methylpyridine, / LCMS ridine hydrochloride (Method): = 6.53 min. [MH]+= 293, 295 26 2- Br Mass Spec: 2-({[2-bromo (chloromethyl)— [MH]+= (methyloxy)phenyl]oxy} 4- 323.9 methyl)—4- (methyloxy)pyr / (methyloxy)pyridine idine Commercial eg ChemBrid-e 27 2- Br Mass Spec: 2-({[2-bromo (chloromethyl)— HO [MH]+= (methyloxy)phenyl]oxy} 4- 307.9 )—4- methylpyridine, / meth lo ridine h drochloride 28 2- Br Mass Spec: (chloromethyl)— HO [MH]+= 1-[3-bromo—4-({[4- 4- 335.9 (methyloxy)—2- (methyloxy)pyr pyridinyl]methyl}oxy)ph en |]ethanone 29 2- Br . LCMS 2-{[(2-bromo (chloromethyl)— (Method B): phenyl)oxy]meth 4- = 7.64 methylpyridine methylpyridine, min, [MH]+= hydrochloride 292, 294 Commercial e... Aldrich 2- . LCMS -bromo (chloromethyl)— H0 (Method A): (ethyloxy)phenyl]oxy}m 4- = 7.59 ethyl)—4-methylpyridine methylpyridine, 0/\ min, [MH]+= hydrochloride Preparation: 322, 324 WO2008079610 31 2- LCMS 2—({[2—bromo (chloromethyl)— HO (Method B): (trifluoromethyl)phenyl] 4- = 7.64 oxy}methyl)—4- methylpyridine, min, [MH]+= methylpyridine hydrochloride F 346, 348 Commercial 99 Fluorochem 32 2- LCMS 3-bromo—4-{[(4-methyl- (chloromethyl)— (Method B): 2- 4- = 6.95 pyridinyl)methyl]oxy}be pyridine, min, [MH]+= nzonitrile hydrochloride 303, 305 33 2- Mass Spec: —bromo(1 ,1- (chloromethyl)— [MH]+= dimethylethyl)phenyl]ox 4- 333.9 y}methyl) pyridine, methylpyridine hydrochloride Commercial eg Apollo Scientific Ltd 71 2- LCMS 3-bromo—N-methyl (chloromethyl)— d B): {[(4-methyl-2— 4- = 6.44 pyridinyl)methyl]oxy}be methylpyridine, min, [MH]+= nzamide hydrochloride 335, 337 72 2- LCMS 3-bromo—4-{[(4-methyl- (chloromethyl)— (Method A): 2- 4- = 6.20 pyridinyl)methyl]oxy}be methylpyridine, min, [MH]+= nzamide hydrochloride 321, 323 73 2- LCMS 3-bromo-N,N-dimethyl- (chloromethyl)— d B): 4-{[(4-methy| 4- = 6.54 pyridinyl)methyl]oxy}be methylpyridine, min, [MH]+= nzamide hydrochloride 349, 351 74 2- LCMS 2—({[2—bromo-3,4- (chloromethyl)— (Method B): bis(methyloxy)phenyl]o 4- = 5.07 xy}methyl) methylpyridine, min, [MH]+= meth lp ridine h drochloride Intermediate 70 338, 340 75 2- LCMS 2-{[(2-bromo (chloromethyl)- (Method A): chlorophenyl)oxy]meth 4- = 7.75 yl}methylpyridine pyridine, Cl min, [MH]+= hydrochloride Commercial e Aldrich 313.85 85 2- 1H 2-bromo—6-methyl (chloromethyl)- (400 MHz, ({[4-(methyloxy) 4- 6) pyridinyl]methy|}oxy)py (methyloxy)pyr 8ppm 8.40 ridine idine (1H, d, CH), 7.52 (1H, d, CH), 7.24 (1H, d, CH), 7.14 (1H, d, CH), 6.96 (1H, 8), 6.95 (1H, m, 1H), .23 (2H, s, CH2), 3.85 (3H, s, OMe), 2.39 86 2- Br LCMS 2-bromo—6-chloro (chloromethyl)- HO (Method A): {[(4-methyl 4- = 6.92 pyridinyl)methyl]oxy}py methylpyridine, /Cl min, [MH]+= ridine hloride 314.85 Commercial e.g. Combi- Blocks lnc. 87 2- LCMS 2-({[2-bromo (chloromethyl) (Method C): (methyloxy)phenyl]0xy} pyrazine Rt = )pyrazine 1.51 min, [MH]+= 295, 296.9 * Intermediate 8 was purified by column chromatography, eluting with 0-20% ethyl acetate in hexane * Purified through silica eluting with a gradient of ethyl acetate in hexane, increasing ethyl acetate until product eluted WO 23311 2012/053948 # Work up by partitioning between ethyl acetate and aqueous ammonium chloride.
Organics dried with sodium sulphate and concentrated in vacuo to yield the title compound.
Intermediate 34 1bromo 4-chloro ridin lmeth lox hen one To a stirred solution of (4-chloropyridinyl)methanol (Commercial eg Aldrich) (0.2g) in THF (5ml) were added 1-(3-bromohydroxyphenyl)ethanone (0.3g) and triphenylphosphine (0.547g). This was stirred for 10 min before cooling and adding slowly DEAD (0.363g). This was stirred for 16h. The reaction mixture was partitioned between water and ethyl acetate. The aqueous was reextracted with ethyl acetate and the combined organics were washed with brine, dried over sodium sulfate and concentrated in vacuo. This was purified through silica eluting with 0-35% ethyl acetate in hexane to give the title nd, 0.30g Mass Spec: [MH]+= 340, 342 Prepared similarly were: sation 1-(3-bromo{5[(4-ethyl- (4-ethyl- Mass Spec pyridinyl)meth [MH]+= 2- anol 333.9 pyridinyl)methyl]oxy}ph enyl)ethanone 36 yI LCMS 2-bromo{[(4-ethyl-2— pyridinyl)meth (Method B): pyridinyl)methyl]oxy}-6— anol = 5.08 methylpyridine min, [MH]+= 307, 309 Intermediate 10: 11-dimeth leth | 7 4-meth l ridin lmeth lox / O N \N To a degassed mixture of 2-bromo{[(4-methyl-2—pyridinyl)methyl]oxy}pyridine (2.83g), 1,1-dimethylethyl 7-(4,4,5,5—tetramethyl-1 ,3,2—dioxaborolan-2—yl)—1,2,4,5— tetrahydro-3H—3-benzazepinecarboxylate (4.54g) and cesium carbonate (9.9g) in dioxane:water (4:1, 40ml) was added PdCI2.dppf (0.828g). The reaction e was heated at 120°C overnight. The reaction mixture was added to water and extraction was carried out with ethyl acetate. The c layer was dried over sodium sulphate and the filtrate was concentrated in vacuo. The crude product was purified through , eluting with 0-40% ethyl acetate in hexane. Appropriate fractions were concentrated in vacuo to yield the title compound, 3.8g (84%).
LCMS (Method A): Rt = 5.70 min, [MH]+ = 446 The following intermediates were similarly prepared: Intermediate ic e sation 0-15% 2. 57g LCMS 1,1-dimethylethyl 7- ethyl (89%) (Method A): (2-(methyloxy)—6—{[(4- acetate in = 6.76 methyl-2— hexane min, [MH]+: pyridinyl)methyl]oxy}p 475 henyl)—1,2,4,5- tetrahyd ro-3H—3- benzazepine carbox late WO 23311 12 0-20% LCMS 1,1-dimethylethyl 7- ethyl (Method A): (4-(methyloxy)—2—{[(4- acetate in = 7.13 hexane min, [MH]+= pyridinyl)methyl]oxy}p 475 henyl)—1,2,4,5- tetrahydro-3H—3- benzazepine carbox late 13 0-20% 3.09 LCMS 1,1-dimethylethyl 7- ethyl (77%) (Method A): (5-acetyl-2—{[(4- acetate in = 6.77 methyl hexane min, [MH]+= pyridinyl)methyl]oxy}p 487 henyl)—1,2,4,5- tetrahydro-3H—3- benzazepine carbox late 14 3.1g LCMS 1,1-dimethylethyl 7- (71%) (Method A): [2-({[4-(methyloxy)—2— Rt = pyridinyl]methy|}oxy)p 6.23min, henyl]—1,2,4,5- [MH]+= 461 tetrahydro-3H—3- benzazepine carbox late 37 Mass Spec: 1,1-dimethylethyl 7- [MH]+= 502 (6—(1,1-dimethylethyl)— 3-{[(4-methyl-2— pyridinyl)methyl]oxy}- 2-pyridinyl)—1,2,4,5- tetrahydro-3H—3- benzazepine carbox late 38 0-40% EA Mass Spec: 1,1-dimethylethyl 7- / hexane [MH]+= hyI{[(4- 460.2 LCMS pyridinyl)methyl]oxy}- (Method A): 2-pyridinyl)—1,2,4,5- = 7.40 tetrahydro-3H—3- min, benzazepine [MH]+=460 carbox late 2012/053948 39 0-20% EA Mass Spec: methylethyl 7- / hexane [MH]+= 474 (3-{[(4-ethyI pyridinyl)methyl]0xy}- 6-methylpyridinyl)— 1,2,4,5-tetrahydro- 3H—3-benzazepine carbox late 40 0-15% EA LCMS 1,1-dimethylethyl 7- / hexane (Method A): (5-methyI{[(4- = 8.21 methyl min, [MH]+= pyridinyl)methyl]0xy}p 459.15 henyl)—1,2,4,5- tetrahydro-3H—3- benzazepine carbox late 41 0-15% EA LCMS 1,1-dimethylethyl 7- / hexane (Method B): hyloxy){[(4- = 8.06 methyl min, [MH]+= pyridinyl)methyl]0xy}p 489.25 henyl)—1,2,4,5- tetrahydro-3H—3- benzazepine carbox late 42 0-25% EA LCMS 1,1-dimethylethyl 7- / hexane (Method A): (5-fluoro{[(4- = 7.97 methyl min, [MH]+= pyridinyl)methyl]0xy}p 463.25 henyl)—1,2,4,5- tetrahydro-3H—3- benzazepine carbox late 43 0-30% EA LCMS 1,1-dimethylethyl 7- / hexanes d B): (5-cyano{[(4- = 7.60 methyl min, [MH]+= pyridinyl)methyl]0xy}p 470.2 henyl)—1,2,4,5- tetrahydro-3H—3- benzazepine carbox late 44 0-37% EA LCMS 1,1-dimethylethyl 7- / hexane (Method A): (5-(1,1-dimethylethyl)— = 8.53 2-{[(4-methy|—2— min, [MH]+= pyridinyl)methyl]oxy}p 501.3 henyl)—1,2,4,5- tetrahydro-3H—3- benzazepine carbox late 45 0-18% EA LCMS 1,1-dimethylethyl 7- / hexane (Method A): [2-{[(4-methy|—2— = 8.06 pyridinyl)methyl]oxy}- min, [MH]+= - 513.2 (trifluoromethyl)pheny |]-1,2,4,5—tetrahydro- enzazepine carbox late 76 0-2% LCMS 1,1-dimethylethyl 7- methanol (Method A): (5- in DCM = 9.03 [(methylamino)carbon min, [MH]+= yl]—2—{[(4-methyl-2— 502 nyl)methyl]oxy}p henyl)—1,2,4,5- tetrahydro-3H—3- benzazepine carbox late 77 0-2% LCMS 1,1-dimethylethyl 7- methanol (Method A): (5-(aminocarbonyl)—2— in DCM = 7.13 {[(4-methyl-2— min, [MH]+= pyridinyl)methyl]oxy}p 488 henyl)—1,2,4,5- tetrahydro-3H—3- benzazepine carbox late 78 0-20% EA/ LCMS 1,1-dimethylethyl 7- hexane (Method A): is(methyloxy)—6— = 6.59 {[(4-methyl-2— min, [MH]+= pyridinyl)methyl]oxy}p 505 —1,2,4,5- tetrah dro-3H—3- benzazepine carboxylate 79 0-25% EA/ LCMS 1,1-dimethylethyl 7- hexane (Method A): (5-chloro{[(4- = 8.17 methyl min, [MH]+= pyridinyl)methyl]oxy}p 479.15 henyl)—1,2,4,5- ydro-3H—3- benzazepine carbox late 88 0-25% EA/ LCMS 1,1-dimethylethyl 7- hexane (Method B): (6-chloro{[(4- = 7.76 methyl min, [MH]+= pyridinyl)methyl]oxy}- 480.15 2-pyridinyl)—1,2,4,5- tetrahydro-3H—3- benzazepine carbox late 89 25% EA/ LCMS 1,1-dimethylethyl 7- hexane (Method C): {2'-(methyloxy)—6'—[(2— = 1.77 nylmethyl)oxy]— min, [MH]+= 4-biphenylyl}-1,2,4,5- 462.2 ydro-3H—3- benzazepine carbox late The following intermediate was prepared rly using 1,1-dimethylethyl 7-(4,4,5,5— tetramethyl-1,3,2-dioxaborolanyl)-3,4-dihydro-2(1H)-isoquinolinecarboxylate rather than 1,1-dimethylethyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)—1,2,4,5— tetrah dro-3H—3-benzazepinecarbox late 90 0-35% EA/ LCMS 1,1-dimethylethyl 7- (Method B): (6-chloro{[(4- = 7.59 methyl min, [MH]+= pyridinyl)methyl]oxy}- 480.15 2-pyridinyl)—3,4- dihydro-2(1H)— isoquinolinecarboxyla Intermediate 15: 11-dimeth leth l 7fluoro 4-meth l \ O / O N O To a degassed mixture 2-{[(2-bromofluorophenyl)oxy]methyl}methylpyridine (0.099), 1,1-dimethylethyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)—3,4-dihydro- 2(1H)-isoquinolinecarboxylate (0.1319) (for preparation see ) and caesium carbonate (0.2969) in e:water (4:1, 5ml) was added PdCI2.dppf (0.0259). The reaction mixture was heated at 120°C ght. The reaction mixture was added to water and extraction was carried out with ethyl acetate. The organic layer was dried over sodium sulphate and the te was concentrated in vacuo. The crude product was purified throu9h silica, eluting with 0-12% ethyl acetate in .
Appropriate fractions were concentrated in vacuo to yield the title compound, 0.1699, quantitative yield.
LCMS (Method B): Rt = 7.95 min, [MH]+ = 449 The following intermediates were similarly prepared: Intermediate Aromatic e tion 46 0.1579 LCMS methylethyl 7-(5- (Method A): methyl{[(4-methyl = 8.20 pyridinyl)methyl]oxy}phen min, [M H]+= y|)-3,4-dihydro-2(1H)— 445.15 isoquinolinecarbox late 47 LCMS 1,1-dimethylethyl 7-(5- (Method A): (methyloxy)—2-{[(4-methyl- = 7.89 2- min, [MH]+= pyridinyl)methyl]oxy}phen 461.2 y|)-3,4-dihydro-2(1H)— isoquinolinecarbox late 48 LCMS 1,1-dimethylethyl 7-[2-{[(4- (Method B): = 8.05 pyridinyl)methyl]oxy} min, [MH]+= (trifluoromethyl)phenyl]— 499.15 3,4-dihydro-2(1H)— isoquinolinecarbox late 49 LCMS 1,1-dimethylethyl 7-(2- d A): (methyloxy)—6—{[(4-methyl- = 7.71 2- min, [MH]+= nyl)methyl]oxy}phen 461 yl)—3,4-dihydro-2(1H)— nolinecarbox late 50 LCMS 1,1-dimethylethyl 7-(5- (Method A): cyano{[(4-methyl = 7.55 pyridinyl)methyl]oxy}phen min, [MH]+= yl)—3,4-dihydro-2(1H)— 456.15 iso.uinolinecarbox late 51 LCMS 1,1-dimethylethyl 7-(5- (Method B): (ethyloxy)—2-{[(4-methyl = 8.05 pyridinyl)methyl]oxy}phen min, [MH]+= yl)—3,4-dihydro-2(1H)— 475 isoquinolinecarboxylate 52 LCMS 1,1-dimethylethyl 7-(5- (Method A): (1 ,1-dimethylethyl)—2-{[(4- = 8.54 methyl min, [MH]+= pyridinyl)methyl]oxy}phen 487.2 yl)—3,4-dihydro-2(1H)— isoquinolinecarbox late 80 LCMS 1,1-dimethylethyl 7-(5- (Method B): [(dimethylamino)carbonyl] = 7.17 {[(4-methy| min, [MH]+= pyridinyl)methyl]oxy}phen 502 yl)—3,4-dihydro-2(1H)— isoquinolinecarbox late 81 LCMS 1,1-dimethylethyl 7-(5- (Method A): (aminocarbonyl)—2—{[(4- = 5.30 methyl-2— min, [MH]+= pyridinyl)methyl]oxy}phen 474 yI)—3,4-dihydro-2(1H)— isoquinolinecarbox late 82 LCMS 1,1-dimethylethyl - d A): bis(methy|oxy)—6—{[(4- = 6.40 methyl-2— min, [MH]+= pyridinyl)methyl]oxy}phen 491 yI)—3,4-dihydro-2(1H)— nolinecarbox late 83 LCMS 1,1-dimethylethyl 7-(5- (Method B): chloro—2—{[(4-methyl-2— = 8.10 pyridinyl)methyl]oxy}phen min, [MH]+= yI)—3,4-dihydro-2(1H)— 465.1 iso.uinolinecarbox late Intermediate 16: 1 1-dimeth leth l 7- 5-acet l 2- razin lmeth lox hen ltetrah dro-3H—3-benzaze ine carboxylate To a stirred solution of 1-{3-bromo—4-[(2—pyrazinylmethyl)oxy]phenyl}ethanone (0.2g) and 1,1-dimethylethyl 7-(4,4,5,5-tetramethyl-1,3,2—dioxaborolan-2—yl)—1,2,4,5- tetrahydro-3H—3-benzazepinecarboxylate (0.34g) in DME (4ml) was added aqueous sodium carbonate (2M, 0.98ml). This was degassed with nitrogen for 15min before adding Tetrakis (37mg). The on was heated under reflux overnight. TLC indicated the reaction had gone to completion and so it was cooled, diluted with water and extracted with ethyl acetate. The ed organics were dried over sodium sulphate and concentrated in vacuo to yield a crude product which was purified by column chromatography, eluting with 0-18% ethyl acetate in hexane. The appropriate ons were concentrated in vacuo to yield the title compound, 0.0939, % yield.
Mass Spec.: [MH]+ = 474.2 Intermediate 17 was similarl ooreared usin. differentaromatic bromides.
Intermediate Aromatic bromide sation 0-18% ethyl Mass Spec 1,1--dimet7hylethyl e in (50.5%) [MH]+: 7-{acetyl---2[(2- hexane 473.2 pyridinylmethyl)o Xyipheny|}- tetrahydro-3H epine carbox late 53 EA/ 0.2479 Mass Spec: 1,1-dimethylethyl hexane [MH]+: 7-{6—methyI[(2- 447.2 pyrazinylmethyl)o xy]pyridinyl}- 1,2,4,5- tetrahydro-3H benzazepine carbox late 54 EA/hexane 0.1939 Mass Spec: 1,1-dimethylethyl [MH]+: 7-{5-(methyloxy)— 462.2 2-[(2- pyrazinylmethyl)o Xyipheny|}- 1,2,4,5- tetrahydro-3H benzazepine carboxylate 55 EA/hexane 0.2689 Mass Spec: 1,1-dimethylethyl [MH]+= 7-[5-(methyloxy)— 491.3 2-({[4- (methyloxy)—2- pyridinyl]methyl}o Xy)pheny|]- tetrahydro—3H—3- benzazepine carbox late 56 EA/hexane 0.2739 Mass Spec: 1,1-dimethylethyl [MH]+= 7-(5-(methyloxy)— 475.3 2-{[(4-methy|—2- nyl)methyl]o Xy}pheny|)- 1,2,4,5- tetrahydro—3H—3- benzazepine carbox late EA/ hexane 0 291 Mass Spec: 1,1-dimethylethyl [MH]+= 7-[5-acetyl({[4- 503.2 loxy)—2- pyridinyl]methyl}o Xy)pheny|]- 1,2,4,5- tetrahydro—3H—3- benzazepine carbox late 58 EA/hexane 0979 Mass Spec: 1,1-dimethylethyl [MH]+= 7-(5-acetyl{[(4- 507.2 chloro—2- pyridinyl)methyl]o Xy}pheny|)- 1,2,4,5- tetrahydro—3H—3- benzazepine carbox late 59 0-4% MeOH 0.217g Mass Spec: methylethyl [MH]+= 7-(5-acetyl{[(4- 501 .2 ethyl pyridinyl)methyl]o Xy}pheny|)- 1,2,4,5- tetrahydro-3H—3- benzazepine carbox late 91 Mass Spec: 1,1-dimethylethyl [MH]+= 7-[6—methyI 476.2 ({[4-(methyloxy)— pyridinyl]methyl}o xy)—2-pyridinyl]— 1,2,4,5- tetrahydro-3H—3- benzazepine carbox late The following intermediate was prepared similarly using methylethyl 7-(4,4,5,5— tetramethyl-1,3,2-dioxaborolanyl)—3,4-dihydro-2(1H)—isoquinolinecarboxylate rather than 1,1-dimethylethyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)—1,2,4,5— tetrah dro-3H—3-benzazeoinecarbox late 84 . Mass Spec: 1,1-dimethylethyl 7-{5- [MH]+= 459.1 [(2- pyridinylmethyl)oxy]phenyl }-3,4-dihydro-2(1H)— is0ouinolinecarbox late The following ediate was prepared similarly using 1,1-dimethylethyl 5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolanyl)—1,3-dihydro-2H-isoindolecarboxylate (Preparation e.g. WO2010145202) rather than 1,1-dimethylethyl 7-(4,4,5,5- tetramethyl-1,3,2-dioxaborolanyl)—1,2,4,5-tetrahydro-3H—3-benzazepine carboxylate 92 . Mass Spec: 1,1-dimethylethyl 5-{5- [MH]+= 473.2 acetyl[(2- nylmethyl)oxy]phenyl }-1 ,3-dihydro-2H— isoindolecarbox late The following intermediate was prepared similarly using 1,1-dimethylethyl 6—(4,4,5,5— tetramethyl-1,3,2—dioxaborolanyl)-3,4-dihydro-2(1H)—isoquinolinecarboxylate (preparation e.g. W02008079277) rather than 1,1-dimethylethyl 7-(4,4,5,5— tetramethyl-1,3,2—dioxaborolan-2—yl)—1,2,4,5-tetrahydro-3H—3-benzazepine carboxylate 93 . Mass Spec: 1,1-dimethylethyl 6—{5- [MH]+= 459.2 acetyl[(2— pyridinylmethyl)oxy]phenyl }-3,4-dihydro-2(1H)— nolinecarbox late Intermediate 60 2-bromo hen lmeth lox ridine To a stirred solution of 6—bromo—3-pyridinol (10g, Commercial eg Apollo Scientific Ltd.) in DMF ) was added ium carbonate (17.8g). The reaction mixture was stirred for 15min at 25-300 before cooling to 15°C. To this was added slowly benzyl bromide (7.5ml) and this was stirred at C for 48h. The reaction mixture was poured into cold water and the solid was collected by filtration to give the title compound, 14.5g Mass Spec: [MH]+ =265.9 Intermediate 61 2- 1 1-dimeth leth l hen lmeth lox ridine To a stirred solution of copper (l) cyanide (18.31g) in dry THF (400ml) was added, at -78C, tertbutylmagnesium de (1M in THF, 409ml). The reaction mixture was stirred at this temperature for 15min before slowly adding a on of 2—bromo [(phenylmethyl)oxy]pyridine (13.5g) in THF. This was stirred for 2h at -78C before warming to 25-300 and stirring for a further 20h. The on mixture was poured into water and extracted with ethyl e. This was concentrated in vacuo and purified through silica, eluting with 0-2% ethyl acetate in hexane. Appropriate fractions were combined and trated in vacuo to yield the title compound, 6.3g LCMS (Method B): Rt = 5.61 min, [MH]+ = 242 Intermediate 62 6- 1 1-dimeth leth l ridinol To a stirred solution of 2-(1,1-dimethylethyl)[(phenylmethyl)oxy]pyridine in , (5.3g) ethanol (150ml) was added 20% Pd(OH)2 (12.3g) at 25-300. The above mixture was purged with hydrogen for 3h until it had gone to completion by tlc. The reaction mixture was filtered through celite and the filtrate concentrated in vacuo and purified to give the title compound, 3.9g LCMS (Method B): Rt = 3.14 min, [MH]+ = 152 To a stirred solution of 6-(1,1-dimethylethyl)—3-pyridinol, (3.8g) in pyridine (150ml) was added bromine (1.29mi), d in pyridine, dropwise at 200. The reaction mixture was allowed to stir at 25-300 for 1h. The reaction had gone to completion by tlc. It was poured into brine and extracted with ethyl acetate. The organics were dried over sodium sulphate and trated under reduced pressure. The crude material was subjected to flash tography using a 0-5% gradient of ethyl e in hexane to give the title compound, 2.9g LCMS (Method B): Rt = 6.16 min, [MH]+ = 229.9 Intermediate 64 11-dimeth leth l 7- 5-acet l 4-eth lox ridin lmeth lox hen ltetrah dro-3H—3-benzaze ine carboxylate Potassium tert-butoxide (0.132g) in ethanol (4ml) was d for 15 min before adding 1,1-dimethylethyl 7-(5-acetyl-2—{[(4-chloropyridinyl)methyl]oxy}phenyl)— 1,2,4,5-tetrahydro-3H—3-benzazepinecarboxylate and this was heated in a , (0.4g) microwave at 1100 for 1.5h. Water (20ml) was added to the cooled mixture and this was extracted with DCM (2 X 30ml). The combined organics were washed with brine, dried over sodium sulphate and concentrated in vacuo. The crude product was ed through silica g with 0-45% ethyl acetate in hexane to give the title compound, 0.16g Mass Spec: [MH]+ = 517.3 Prepared rly was Intermediate: Intermediate Starting Materials LCMS 94 Mass Spec: 1,1-dimethylethyl [MH]+: 547.3 7-(5-acetyl-2—{[(4- {[2- (methyloxy)ethyl] oxy}-2— pyridinyl)methyl]o xy}phenyl)— 1,2,4,5- tetrahydro-3H MeO(CH2)2OH benzazepine carbox late Exam le 1: 7 4-meth l ridin lmeth lox ridin l tetrahydro-1Hbenzazepine / O N \ N 1,1-dimethylethyl 7-(3-{[(4-methyl-2—pyridiny|)methyl]oxy}pyridinyl)-1,2,4,5- tetrahydro-3H—3-benzazepinecarboxylate (3.8g) was dissolved in dioxane .
Gaseous hydrogen chloride was passed through the reaction e for 1.5h. The reaction was monitored by TLC. On completion the solid formed was collected by tion and washed with acetone. The solid was then dissolved in water and the mixture neutralised with aqueous sodium hydroxide (1M). The sticky solid formed was extracted with DCM. The organic phase was dried over sodium sulphate and concentrated in vacuo to give a solid. This was purified through silica, eluting the product with 0-12% methanol in DCM. The solid from this was triturated in l ether to give the title compound, 2g (69%) yield.
LCMS (Method A): Rt = 3.25 min, [MH]+ = 346 NMR 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.43ppm (1H, d, CH), 8.27ppm (1H, d, CH), 7.77ppm (1H, s, CH), 7.70-7.64ppm (2H, 2Xd, 2XCH), 7.35ppm (2H, m, 2XCH), 7.20ppm (2H, m, 2XCH), m (2H, s, CH2), 2.97ppm (8H, br.m, 4XCH2), 2.32ppm (3H, s, CH3) 2,3,4,5-tetrahydro-1Hbenzazepine \ I N/ O l O\ 1,1-dimethylethyl 7-(2-(methyloxy){[(4-methylpyridinyl)methyl]oxy}phenyl)— 1,2,4,5-tetrahydro-3H—3-benzazepinecarboxylate (2.57g) was dissolved in dioxane (20ml). Gaseous hydrogen de was passed through the reaction mixture for about 1.5h. The reaction was red by TLC. On completion the solid formed was collected by filtration and washed with acetone. The solid was then dissolved in water and the mixture lised with aqueous sodium hydroxide (1M). The sticky solid formed was extracted with DCM. The c phase was dried over sodium sulphate and concentrated in vacuo to give a solid. This was purified by silica column chromatography eluting with 0-8% methanol in DCM. The appropriate fractions were ed and concentrated in vacuo to yield a solid. This was triturated with diethyl ether to yield the title compound, 1.34g (67%).
LCMS (Method A): Rt = 3.89 min, [MH]+ = 375 NMR 1H NMR (400 MHz, 6) 5 ppm 8.35ppm (1H, d, CH), 7.24ppm (1H, m, CH), 7.21-7.08ppm (4H, m, 4XCH), 6.94ppm (1H, br.s, CH), 6.78ppm (2H, m, 2XCH), m (2H, s, CH2), 3.68ppm (3H, s, OCH3), 3.09ppm (8H, br.m, 4XCH2), 2.23ppm (3h, 8, CH3) Exam le 2A 7meth lox 4-meth l ridin lmeth lox hen l- 2,3,4,5-tetrahydro-1Hbenzazepine methanesulfonate 7-(2—(methyloxy){[(4-methylpyridinyl)methy|]oxy}phenyl)-2,3,4,5-tetrahydro-1H- 3-benzazepine (300.0mg; 1.0eq) was weighed into a 20-mL vial containing a stir bar and combined with 2—propanol (6.0mL). The suspension was heated to 40°C and stirred for 15min (solids dissolved). Seeds of the methanesulfonate salt were added (~1mg). Methanesulfonic acid (3M in water; 1.1eq.; 293.0uL in aliquots: 43, 50, 100, and 100uL) was added. White solid precipitated after the first aliquot (43uL). The sion was re-seeded with the methansulfonate salt (~1mg). After all aliquots of the rion solution were added, the suspension was stirred at 40°C for 1hr. The suspension was cooled to 5°C at 0.5°C/min and stirred for 15min. The product was isolated on a Biichner funnel using #1 Whatman filter paper, air-dried for 30min, and dried at 40°C under vacuum for 12hrs. The title compound was produced as a white crystalline powder. A yield of 82% was obtained.
Exam le 3: 7meth lox 4-meth l ridin lmeth lox hen l- 2,3,4,5-tetrahydro-1Hbenzazepine \ l / O N D 1,1-dimethylethyl 7-(4-(methyloxy){[(4-methylpyridinyl)methyl]oxy}phenyl)— 1,2,4,5-tetrahydro-3H—3-benzazepinecarboxylate (4.8g) was ved in dioxane (20ml). Gaseous hydrogen chloride was passed through the reaction mixture for 1.5h. The reaction was monitored by TLC. On tion the solid formed was collected by filtration and washed with e. The solid was then dissolved in water and the mixture was brought to pH8 using s sodium bicarbonate. The sticky solid observed was extracted with DCM. The organics were dried over sodium sulphate and concentrated in vacuo to yield a solid. This was purified by column tography eluting with 0-8% methanol in DCM. Appropriate fractions were combined and concentrated in vacuo to yield a solid. This was triturated in diethyl ether to yield the title compound, 1.7g (45%).
LCMS (Method A): Rt = 4.11 min, [MH]+ = 375 NMR1H NMR (400 MHz, DMSO-d6) 5 ppm 8.41ppm (1H, d, CH), 7.38ppm (1H, brs, CH), 7.29-7.23ppm (3H, m, 3XCH), 7.19—7.15ppm (2H, m, 2XCH), 6.76ppm (1H, br.s, CH), 6.63ppm (1H, d, CH), 5.14ppm (2H, s, CH2), 3.79ppm (3H, s, OCH3), 3.00ppm (8H, br.m, 4XCH2), 2.30ppm (3H, s, CH3) Exam le 4: 1 4-meth l ridin lmeth lox 2345-tetrah dro-1H benzaze in l hen lethanone 1,1-dimethylethyl cetyl{[(4—methylpyridinyl)methy|]oxy}phenyl)-1,2,4,5- tetrahydro-3H—3-benzazepinecarboxylate (3.0g) was dissolved in dioxane (20ml).
Gaseous hydrogen chloride was passed through the reaction mixture for 1.5h. The reaction was monitored by TLC. On completion the solid formed was collected by filtration and washed with acetone. The solid was then ved in water and the mixture neutralised with aqueous sodium hydroxide (1M). Solid was obtained which was ted by filtration. This was triturated with l ether to yield the title compound, 2.1g (88%).
LCMS (Method A): Rt = 3.77 min, [MH]+ = 387 NMR 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.42ppm (1H, d, CH), 7.98ppm (1H, d, CH), 7.95ppm (1H, s, CH), 7.42ppm (1H, br.s, CH), 7.36—7.30ppm (2H, m, 2XCH), 7.25-7.17ppm (3H, m, 3XCH), 5.26ppm (2H, s, CH2), 2.94ppm (8H, m, 4XCH2), 2.57ppm (3H, s, CH3), 2.26ppm (3H, s, CH3) ed similarly were the following examples: WStarting Material Characterisation Mass Spec.: [MH]+ = 360.1 HPLC: Rt = 5.28 7-(6—methyl min {[(4-methyl-2— pyridinyl)methyl]o xy}pyridinyl)- 2,3,4,5- tetrahyd ro-1H—3- eo ine Exam le 5: 1 2- razin lmeth lox 2345-tetrah dro-1Hbenzaze in- 7- l hen lethanone trifluoroacetate t 0 [NEW To a stirred on of 1 ,1-dimethylethyl 7-{5-acetyl[(2- pyrazinylmethyl)oxy]phenyl}-1,2,4,5-tetrahydro-3Hbenzazepinecarboxylate (0.0939) in DCM (2ml) at 0°C was added dropwise trifluoroacetic acid (0.08ml). This was stirred at room temperature overnight. The reaction had gone to completion by TLC and so was concentrated in vacuo and azeotroped with diethyl ether (5 X 10ml).
The compound obtained was washed with diethyl ether and pentane to yield a crude compound that was purified by preparative HPLC. Appropriate fractions were concentrated in vacuo to yield the title compound as the TFA salt, 0.0409.
NMR 1H NMR (400 MHz, DMSO-ds) 8 ppm 8.88 (br. s., 2 H), 8.71 (s, 1 H), 8.68 (d, J=2.3 Hz, 1 H), 8.62 (d, J=2.3 Hz, 1 H), 8.00 (dd, J=8.6, 2.0 Hz, 1 H), 7.89 (d, J=2.3 Hz, 1 H), 7.49 (s, 1 H), 7.45 (d, J=7.8 Hz, 1 H), 7.38 (d, J=8.8 Hz, 1 H), 7.29 (d, J=7.8 Hz, 1 H), 5.41 (s, 2 H), 3.19 - 3.27 (m, 4 H), 3.04 - 3.17 (m, 4 H), 2.58 (s, 3 H) Mass Spec.: [MH]+ = 374.1 Exam le 6: 7fluoro 4-meth l ridin lmeth lox hen l tetrahydroisoguinoline \ l / O N O 1,1-Dimethylethyl 7-(5-fluoro{[(4-methylpyridinyl)methyl]oxy}phenyl)—3,4- dihydro-2(1H)-isoquinolinecarboxylate (0.1699) was dissolved in dioxane (1ml). This was ice cooled before adding dropwise a solution of hydrogen chloride in dioxane (2ml). This was stirred at room temperature overnight before concentrating in vacuo.
The residue obtained was ved in water and backwashed with ethyl acetate. The aqueous layer was neutralised with aqueous sodium hydroxide (1M) and extracted with ethyl e. The or9anics were concentrated in vacuo and ed by preparative HPLC. Appropriate ons were concentrated, neutralised with aqueous sodium bicarbonate and extracted with ethyl acetate. The cs were concentrated in vacuo to yield the title compound, 0.0619 (47%).
LCMS (Method A): Rt = 6.37 min, [MH]+ = 349 ed similarly were the following examples: 72mg LCMS (Method 7-(5—methyl-2— B): Rt = 6.61 min, {[(4-methyI [MH]+: 345 pyridinyl)methyl]o Xy}pheny|)- 1,2,3,4- tetrahydroisoquin oline 11 )L LCMS (Method 7-(2—(methyloxy)— B): Rt = 6.06 min, 6-{[(4-methy|-2— [MH]+: 361.1 pyridinyl)methyl]o ny|)- 1,2,3,4- tetrahydroisoquin oline 12 LCMS (Method 7-(5-(ethyloxy)—2— A): Rt = 6.59 min, ethyI [MH]+: 375 pyridinyl)methyl]o Xy}pheny|)- 1,2,3,4- tetrahydroisoquin oline 14 LCMS (Method 4-{[(4-methyl-2— A): Rt = 5.94 min, pyridinyl)methyl]o [MH]+= 356 xy}(1,2,3,4- tetrahydro isoquinolinyl)ben zonitrile WO 23311 LCMS (Method 7-[2-{[(4-methy|- B): Rt = 6.72 min, 2- [MH]+= 399.1 pyridinyl)methyl]o xy} (trifluoromethyl)p henyl]—1,2,3,4- ydroisoquin oline 16 LCMS (Method 7-(5-(methyloxy)— A): Rt = 6.18 min, 2-{[(4-methyI [MH]+= 361.1 pyridinyl)methyl]o Xy}pheny|)- tetrahydroisoquin oline 17 LCMS (Method 1 ,1- B): Rt = 7.10 min, dimethylethy|) [MH]+= 387.2 {[(4-methyI pyridinyl)methyl]o Xy}pheny|)- 1,2,3,4- tetrahydroisoquin oline 39 LCMS (Method N-methyI{[(4- A): Rt = 5.38 min, methyl [MH]+= 402 pyridinyl)methyl]o xy}(2,3,4,5- tetrahyd ro-1H—3- benzazepin | benzamide 40 LCMS (Method 4-{[(4-methyI B): Rt = 5.21 min, pyridinyl)methyl]o [MH]+= 388 xy}(2,3,4,5- tetrahyd ro-1H—3- benzazepin y|)benzamide 41 LCMS (Method N,N-dimethyI A): Rt = 5.43 min, {[(4-methyI [MH]+= 402 nyl)methyl]o xy}(1,2,3,4- tetrahyd ro isoquinolinyl)ben zamide 42 LCMS (Method 4-{[(4-methy|-2— A): Rt = 3.01 min, pyridinyl)methyl]o [MH]+= 374 xy}(1,2,3,4- tetrahyd ro isoquinolinyl)ben zamide 43 LCMS (Method 7-(2,3- A): Rt = 3.49 min, bis(methy|oxy)—6— [MH]+= 391 {[(4-methyI pyridinyl)methyl]o ny|)- 1,2,3,4- tetrahydroisoquin oline 44 LCMS (Method 7-(2,3- A): Rt = 3.56 min, bis(methy|oxy)—6— [MH]+= 405 ethyI pyridinyl)methyl]o Xy}pheny|)- 2,3,4,5- tetrahyd ro-1H—3- benzazepine Exam le 7: tetrahydro-1Hbenzazepine To a stirred on of 1,1-dimethylethyl 7-[2-({[4-(methyloxy)—2— pyridinyl]methyl}oxy)phenyl]-1,2,4,5—tetrahydroH-benzazepinecarboxylate (3.0g) in dioxane (30ml) was added hydrogen chloride gas for 2h at 10-20°C. This was trated in vacuo. The e was dissolved in water, washed with ethyl acetate and basified by adding aqueous sodium bicarbonate. This was extracted with % methanol in DCM. The organics were dried over sodium sulphate and trated in vacuo to yield the title compound, 2.14g (91%).
LCMS (Method B): Rt = 6.18 min, [MH]+ = 361 Exam le 8: 1 2- ridin lmeth lox 5-tetrah dro-1Hbenzaze in- 7- l hen lethanone trifluoroacetate \ I / O N O To a cooled, stirred solution of 1,1-dimethylethyl 7-{5-acetyl[(2— pyridinylmethyl)oxy]phenyl}-1,2,4,5-tetrahydro-3H—3-benzazepinecarboxylate (0.056g) in DCM (1ml) was added TFA (0.2ml). This was stirred overnight. The reaction had gone to completion and so was concentrated in vacuo and tritutrated with pentane/ether to yield the title compound as the TFA salt, 0.028g (63.6%).
Mass Spec.: [MH]+ = 373.1 HPLC: Rt= 5.71 min.
Prepared similarly were the following examples: WStarting Material Characterisation 18 100mg HPLC Rt= 5.51 7-{6-methyI[(2- min pyrazinylmethyl)o Mass Spec: xy]pyridiny|}- [MH]+= 347.1 234.5- tetrahyd ro—1H—3- benzazepine, trifluoroacetate 19 22mg HPLC Rt= 5.23 7-(6-methyI min {[(4-methyI Mass Spec: nyl)methy|]o [MH]+= 360.1 xy}-2—pyridiny|)— tetrahyd ro—1H—3- benzazepine, oroacetate 80mg HPLC Rt= 8.00 7-{5-(methyloxy)— min 2—[(2— Mass Spec: pyrazinylmethyl)o [MH]+= 362.1 Xylpheny|}- 2,3,4,5- tetrahyd ro—1H—3- benzazepine, trifluoroacetate 21 HPLC Rt= 6.88 7-[5-(methyloxy)— min 2—({[4- Mass Spec: (methyloxy)—2— [MH]+= 391.1 pyridinyl]methyl}o Xy)pheny|]- 2,3,4,5- tetrahyd ro—1H—3- benzazepine 22 HPLC Rt= 6.89 7-(5-(methyloxy)— min 2-{[(4-methy|—2- Mass Spec: pyridinyl)methy|]o [MH]+= 375.1 Xy}pheny|)- 2,3,4,5- tetrahyd ro—1H—3- epine, trifluoroacetate (TFA salt of exam o |e 29 23 HPLC Rt= 6.55 1-[4-({[4- min (methyloxy)—2- Mass Spec: pyridinyl]methyl}o [MH]+= 403.2 xy)—3-(2,3,4,5- yd ro—1H—3- benzazepin y|)pheny|]ethano 24 HPLC Rt= 5.65 [(4-methy|— min 2- Mass Spec: pyridinyl)methy|]o [MH]+= 387.1 xy}(2,3,4,5- tetrahyd ro—1H—3- benzazepin y|)pheny|]ethano trifluoroacetate (TFA salt of example 4) HPLC Rt= 5.92 7-[2-({[4- min (methyloxy)—2- Mass Spec: pyridinyl]methyl}o [MH]+= 361.1 Xy)pheny|]- 2,3,4,5- tetrahyd ro—1H—3- benzazepine, trifluoroacetate 47 HPLC Rt= 4.35 7-[6—methyl min ({[4-(methyloxy)— Mass Spec: 2- [MH]+= 376.1 nyl]methyl}o xy)—2—pyridinyl]— 2,3,4,5- tetrahyd ro-1H benzazeoine Exam le 26 7- 5-fluoro 4-meth l ridin lmeth lox hen l-2 345- tetrahydro-1Hbenzazepine 1,1-dimethylethyl luoro{[(4-methylpyridinyl)methyl]oxy}phenyl)—1,2,4,5- tetrahydro-3H—3-benzazepinecarboxylate, (0.304g) was dissolved in a minimum amount of dioxane. The solution was cooled in ice and to this was added a solution of HCI in dioxane (2ml). This was stirred until the reaction had gone to completion by tlc. The reaction e was concentrated in vacuo. The product salt was ved in water and backwashed with ethyl acetate. The aqueous was neutralised with aqueous sodium hydroxide (1M). This was extracted with ethyl acetate. The organics were dried over sodium sulphate and concentrated to give the title compound, 100mg.
LCMS (Method B): Rt = 6.34 min, [MH]+ = 363.1 Prepared similarly were the following examples: 27 LCMS (Method 7-(5-methyI B): Rt = 6.67 min, {[(4-methyI [MH]+= 359.2 nyl)methyl]o ny|)- 2,3,4,5- tetrahyd ro-1H—3- benzazepine 28 LCMS d 7-(5-(ethyloxy) A): Rt = 6.59 min, {[(4-methyI [MH]+= 389.2 pyridinyl)methyl]o Xy}pheny|)- 2,3,4,5- yd ro-1H—3- benzazeo ine 29 LCMS (Method 7-(5-(methyloxy)— A): Rt = 6.22 min, 2-{[(4-methyI [MH]+= 375.1 pyridinyl)methyl]o Xy}pheny|)- 2,3,4,5- tetrahyd ro-1H—3- benzazeo ine LCMS (Method 4-{[(4-methyI A): Rt = 5.82 min, pyridinyl)methyl]o [MH]+= 370.1 xy}(2,3,4,5- tetrahyd ro-1H—3- benzazepin | benzonitrile 31 LCMS (Method 7-[2-{[(4-methy|- A): Rt = 6.67 min, 2- [MH]+= 413.1 pyridinyl)methyl]o xy}-5— (trifluoromethyl)p heny|]-2,3,4,5- tetrahyd ro-1H—3- benzazepine 32 LCMS (Method 7-(5-(1,1- B): Rt = 7.08 min, dimethylethy|) [MH]+= 401.2 {[(4-methyl-2— pyridinyl)methyl]o ny|)- 2,3,4,5- tetrahyd ro-1H—3- benzazeoine 45 . LCMS d 7-(5-chloro-2— B): Rt = 6.71 min, ethyI [MH]+= 379 pyridinyl)methyl]o Xy}pheny|)- 2,3,4,5- tetrahyd ro-1H—3- benzazepine tetrahydro-1Hbenzazepine El/ o N |\N To a stirred on of 1,1-dimethylethyl 7-(3-{[(4-ethyl-2—pyridinyl)methyl]oxy}-6— pyridinyl)—1,2,4,5-tetrahydro-3H—3-benzazepinecarboxylate, (4.3g) in dioxane (30ml) was passed through HCI (gas) for 30 min at 20°C. After completion of reaction by TLC, the solvent was removed in vacuo .The solid obtained was washed with acetone and dissolved in water. This was neutralised with sodium bicarbonate, extracted with DCM and and concentrated in vacuo to give a crude product. This was purified through silica using 6% methanol in DCM. Appropriate fractions were combined and concentrated in vacuo to give a product. This was triturated in diethyl ether to yield the title compound, 1.5g.
LCMS (Method B): Rt = 3.29 min, [MH]+ = 374 The following example was prepared similarly: 34 >L0 2.79 LCMS (Method 7-(6-(1,1- N >T B): Rt = 4.73 min, dimethylethyl)—3- [MH]+= 402 {[(4-methyl-2— pyridinyl)methyl]o xy}pyridinyl)- 2,3,4,5- yd ro-1H—3- benzazepine Exam le 35 1 4-eth l ridin lmeth lox 2 trah dro-1H benzaze in l hen lethanone / O N O To a solution of 1,1-dimethylethyl 7-(5-acetyl-2—{[(4-ethyl pyridinyl)methyl]oxy}phenyl)—1,2,4,5-tetrahydro-3H—3-benzazepinecarboxylate, (0.2179) in DCM (3ml) was added TFA (0.4ml). This was stirred at room temperature.
After tion of reaction by tlc, the reaction mixture was concentrated in vacuo and purified by preparative hplc. Product fractions were concentrated in vacuo and the product obtained was partitioned between DCM and aqueous sodium bicarbonate. The organics were dried over sodium te and concentrated in vacuo to yield the title compound, 0.0359 LCMS (Method A): Rt = 5.28 min, [MH]+ = 401.05 HPLC: 6.89min.
Exam le 36 1 4-eth lox ridin l meth l ox 2 3 4 5-tetrah dro- 1Hbenzaze in l hen lethanone To a stirred solution of 1,1-dimethylethyl 7-[5-acetyl-2—({[4-(ethyloxy)—2— pyridinyl]methyl}oxy)phenyl]—1,2,4,5-tetrahydro-3H—3-benzazepinecarboxylate, (0.169) in DCM (2ml) at 0C was added TFA (0.2479). This was d at room temperature for 16h before concentrating and purifying by preparative hplc. The title compound was isolated as the TFA salt, 0.0589 Mass Spec: [MH]+ = 417.2 HPLC: n.
Similarly prepared was example 50: Characterisation [(4-{0[2- 0.0459 HPLC Rt= 6.66 (methyloxy)ethyl] Mass Spec: oxy}-2— [MH]+: 447 pyridinyl)methyl]o xy}(2,3,4,5- tetrahyd ro-1H—3- benzazepin yl)phenyl]ethano Exam le 37 7- 5- meth lox 2- ridin lmeth lox hen l tetrahydro-1Hbenzazepine WO 23311 (lll/O ”OO/ (3-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro—1Hbenzazepinyl)boronic acid (Preparation in WO2004056369) (0.1259) was added to a stirred solution of R19158/5/TC-1, 2-({[2-bromo(methyloxy)phenyl]oxy}methyl)pyridine, (0.0859) in DME (2ml) under an argon atmosphere at room temperature. After 1 min, aqueous sodium carbonate (2M, 3 mole equiv.) was added. After 2 min, tetrakis (0.0169) was added and this was heated at 90C until completion of the reaction by tlc. The crude product was partitioned between DCM and water. The aqueous was reextracted twice with DCM. The combined or9anics were dried over sodium te, filtered and concentrated in vacuo to yield a crude product. This was purified by column chromatography (silica) using a nt of ethyl e in cyclohexane to yield the BOC-protected product. This was stirred in a solution of HCI in ethyl acetate until reaction had gone to completion by tlc. This yielded the title compound as the hydrochloride salt, 0.039.
Mass Spec: [MH]+ = 361.1 HPLC: 6.06min.
Exam le 38 1 2- ridin lmeth lox 1234-tetrah dro iso uinolin l hen one 0 To a solution of1,1-dimethylethyl 7-{5-acetyl[(2-pyridinylmethyl)oxy]phenyl}-3,4- dihydro-2(1H)-isoquinolinecarboxylate ) in dioxane was added a solution of HCI in dioxane (5ml). The reaction mixture was stirred at room temperature until it was complete (by TLC). It was concentrated in vacuo and the residue was purified by preparative hplc to yield the title nd as the TFA salt, 0.0559.
Mass Spec: [MH]+ = 359.1 HPLC: n.
Exam le 46 7- 5-chloro 2- ridin lmeth lox hen l -12 34- tetrahydroisoguinoline / O N 0 To an ice cooled solution of, 1,1-dimethylethyl 7-(5—chloro{[(4-methyl-2— pyridinyl)methyl]oxy}phenyl)—3,4-dihydro-2(1H)—isoquinolinecarboxylate, (0.28g) in DCM (1ml) was added TFA (1ml) and this was stirred at room temperature ght.
The reaction e was dissolved in water and backwashed with ethyl acetate. The aqueous layer was neutralised with aqueous sodium bicarbonate and extracted with ethyl acetate. The organics were dried over sodium sulphate and concentrated in vacuo to yield the title compound, 0.12g LCMS (Method A): Rt = 6.66 min, [MH]+ = 365 Exam le 48 7chloro 4-meth l ridin lmeth lox ridin l- 2,3,4,5-tetrahydro-1Hbenzazepine / o N \N To an ice cooled solution of1,1-dimethylethyl 7-(6-chloro{[(4-methyl-2— pyridinyl)methyl]oxy}-2—pyridinyl)—1 ,2,4,5-tetrahyd 3-benzazepinecarboxylate in DCM (1ml) was added dropwise TFA (1ml) and the reaction mixture stirred at room temperature until the starting material had been consumed. The reaction e was concentrated in vacuo, dissolved in water and backwashed with ethyl acetate. The 2012/053948 aqueous layer was neutralised with aqueous sodium bicarbonate then extracted with ethyl acetate, dried over sodium sulphate and concentrated in vacuo to yield the title compound, 27mg.
LCMS (Method A): Rt = 6.33 min, [MH]+ = 380.1 Prepared similarly were the following examples: WStarting Material Characterisation LCMS (Method ch|oro B): Rt = 6.30 min, {[(4-methyl-2—- [MH]+: 366.1 pyridinyl)methyl]o xy}pyridinyl)- 1,2,3,4- ydroisoquin oline 51 . HPLC Rt= 5.46 1-{3-(2,3-dihydro— min 1H—isoindolyl)— Mass Spec: 4-[(2- [M H]+= pyridinylmethyl)o xy]phenyl}ethano 52 . HPLC Rt= 5.57 1-[4-[(2- min pyridinylmethyl)o Mass Spec: xy](1,2,3,4- [MH]+: 359.1 tetrahydro isoquinolinyl)phe nyl]ethanone Exam le13 7- 2-meth lox 2- razin lmeth lox hen l tetrah dro-1Hbenzaze ine h drochloride WO 23311 N O [LN/ O I 0\ To a solution of 1,1-dimethylethyl 7-{2'—(methyloxy)—6'-[(2-pyrazinylmethyl)oxy] biphenylyl}-1,2,4,5-tetrahydro-3Hbenzazepinecarboxylate (1 .09) in DCM was bubbled dry HCI gas for 2 hours. The solvent was removed under reduced pressure and the e was washed with diethyl ether. The precipitated solid was ted by filtration to give the title compound, 0.7009 LCMS (Method C): Rt = 1.49 min, [MH]+ = 362.2 Pre aration of Pol mor hic forms of 7- 2- meth lox 4-meth l ridin l meth lox hen l -2 3 4 5-tetrah dro-1Hbenzaze ine Form 1 The crystalline form of7-(2-(methyloxy)—6—{[(4-methylpyridinyl)methyl]oxy}phenyl)— 2,3,4,5-tetrahydro-1Hbenzazepine was produced by a scale up 89 of the method used to produce the compound of Example 2A. It was terised by one or more of the methods described below and was designated as Form 1.
Preparation of Form 2 Batch 1 40.0mg of the Form 1 was combined with 1 mL of de water, mixed and temperature-cycled from 40°C to 5°C for 72 hours, then equilibrated at 20°C for 1 hour. The solids were isolated from the filtrate by vacuum-filtration on a stainless steel analytical plate with 10” — 15” vacuum at RT for ~30 minutes.
Preparation of Form 2 Batch 2 237mg of the input material was combined with 4mL of HPLC-grade water. The slurry was seeded and thermocycled from 40°C to 5°C over 20 hours. Raman assay of a filtered aliquot showed Form 2. Solids were filtered by vacuum and dried in a vacuum oven at 20” vacuum and 40°C for 4 hours. Yield= 197.6mg. 150mg of Form 1 was combined with 3mL of HPLC-grade water and stirred at RT (~23°C) for 18 hours. A small aliquot was withdrawn, ed, and assayed by Raman. The spectrum was consistent with Form 1. The slurry was seeded with Form 1 and stirred at 40°C for 4 hours. Raman assay of a filtered aliquot showed a mixture of Form 1 and Form 2 with approximately 30% Form 2. The slurry was thermocycled from 40°C to 5°C over 72 hours. Raman assay of a ed aliquot showed only Form 2. The rest of the slurry was filtered. Raman assay of the isolated solid showed only Form 2. The filtered sample was dried at 30°C with 20" vacuum for 3.5 hours. Raman assay showed only Form 1 consistent with batch 1.
Dried yield= 95mg.
Characterisation methods Powder X-ray diffractograms were acquired using either a PANalytical X’Pert Pro ctometer on Si ackground wafers. All diffractograms were collected using a monochromatic Cu Ka (45 kVI40 mA) radiation and a step size of 0.02°20. Peak positions were determined using Highscore software and the margin of error in peak positions is approximately i0.1°20.
Figure 1 shows the XRPD diffraction pattern for FORM 1. Table 1 shows the main degrees 2 theta peaks ed for FORM 1.
Figure 4 shows the XRPD ction pattern for FORM 2. Table 2 shows the main degrees 2 theta peaks observed for FORM 2.
Table 3 shows the distinguishing features between the XRPD diffraction pattern for FORM 1 and FORM 2.
Table 1 XRPD peak positions for Form 1 Position I Position I °20 d-spacing IA d-spacing IA 11.7 7.5 23.0 3.9 12.7 7.0 23.7 3.8 13.7 6.5 24.0 3.7 14.6 6.1 24.4 3.6 16.0 5.5 25.1 3.5 17.8 5.0 25.5 3.5 18.9 4.7 26.1 3.4 19.4 26.9 3.3 .2 27.5 3.2 21.2 . 28.1 3.2 22.6 Table 2 XRPD peak positions for Form 2 P08' Ion /'t' Position I °20 d-spacing IA d-spacing IA 21.3 4.2 22.9 3.9 23.1 3.8 2012/053948 Table 3 XRPD peak d-spacino IA 13.3 FT-Raman oscopy Raman spectra were collected with a Nicolet NXR9650 (Thermo Electron) equipped with 1064 nm Nd:YVO4 excitation laser, lnGaAs and liquid-N2 cooled Ge detectors, and a tage. All spectra were acquired at 4 cm'1 resolution, 64-128 scans, using Happ-Genzel ation function and 2-level zero-filling. Band positions were determined using Omnic software and the margin of error in band positions is approximately i1cm'1.
Figure 2 showns the FT-Raman Spectrum for FORM 1. Table 4 shows the main peaks observed for FORM 1.
Figure 5 shows the FT-Ramen Spectrum for FORM 2. Table 5 shows the main peaks observed for FORM 2.
Table 6 shows the distinguishing features between the Raman Spectra for FORM 1 and FORM 2.
Table 4 Raman band positions for Form 1 Position/cm'1 202 562 1464 226 570 1177 1569 250 m- 1189 1610 312 715 1208 2832 354 766 1236 2865 Raman band positions for Form 2 Position /cm-1 1210 2957 1242 2973 316 748 Differential Scanning Calorimetry (DSC) Differential scanning calorimetry was conducted with a ruments Q100 differential ng calorimeter equipped with an autosampler and a refrigerated cooling system under 40 mL/min N2 purge. DSC thermograms were obtained at 15°C/min in crimped AI pans.
Figure 3 shows the DSC thermogram of FORM 1.
Figure 6 shows DSC thermogram of FORM 2.

Claims (24)

Claims
1. A compound of formula (I): wherein: X is CR1 or N; Y is CH, C or N; 10 R1 is hydrogen, Cmalkoxy or Cmalkyl; R2 is hydrogen, C145alkoxy, halo, -C(O)CH;alkyl, CN, Halo-Gwalkyl or C(O)NR4R5; R3 is hydrogen or C145alkoxy; R4 is hydrogen or Cmalkyl: R5 is hydrogen or C14;allwl and 15 m and n are integers each independently selected from 1 and 2; or a salt thereof.
2. A nd ing to claim 1, wherein the compound is a compound of formula (la): wherein: X is CR1 or N; Y is CH, C or N; 25 R1 is hydrogen, Cmalkoxy or Cmalkyl; R2 is hydrogen, C145alkoxy, halo or -C(O)C15alkyl; and m and n are integers each independently selected from 1 and 2; or a salt thereof.
3. A compound or a salt thereof according to claim 1 or claim 2 wherein X is CR1.
4. A compound or a salt thereof according to claim 3 wherein R1 is , methoxy or hydrogen.
5. A compound or a salt thereof according to any one of claims 1 to 4 wherein Y is C.
6. A compound or a salt thereof according to any one of claims 1 to 5 wherein R2 is en, methoxy or -C(O)CH3.
7. A compound or a salt f according to any one of claims 1 to 6 wherein m and n are both 2.
8. A compound according to claim 1 which is ed from: 7-(3-{[(4-methylpyridinyl)methyl]oxy}pyridinyl)-2,3,4,5-tetrahydro-1H benzazepine; 7-(2-(methyloxy){[(4-methylpyridinyl)methyl]oxy}phenyl)-2,3,4,5-tetrahydro-1H- 3-benzazepine; methyloxy){[(4-methylpyridinyl)methyl]oxy}phenyl)-2,3,4,5-tetrahydro-1H- 3-benzazepine; 1-[4-{[(4-methylpyridinyl)methyl]oxy}(2,3,4,5-tetrahydro-1Hbenzazepin yl)phenyl]ethanone; 1-[4-[(2-pyrazinylmethyl)oxy](2,3,4,5-tetrahydro-1Hbenzazepin yl)phenyl]ethanone; 7-(5-fluoro{[(4-methylpyridinyl)methyl]oxy}phenyl)-1,2,3,4- tetrahydroisoquinoline; 7-[2-({[4-(methyloxy)pyridinyl]methyl}oxy)phenyl]-2,3,4,5-tetrahydro-1H benzazepine; 1-[4-[(2-pyridinylmethyl)oxy](2,3,4,5-tetrahydro-1Hbenzazepin yl)phenyl]ethanone; 7-(6-methyl{[(4-methylpyridinyl)methyl]oxy}pyridinyl)-2,3,4,5-tetrahydro-1H benzazepine; 7-(5-methyl{[(4-methylpyridinyl)methyl]oxy}phenyl)-1,2,3,4- tetrahydroisoquinoline; 7-(2-(methyloxy){[(4-methylpyridinyl)methyl]oxy}phenyl)-1,2,3,4- tetrahydroisoquinoline; 7-(5-(ethyloxy){[(4-methylpyridinyl)methyl]oxy}phenyl)-1,2,3,4- tetrahydroisoquinoline; 7-{2-(methyloxy)[(2-pyrazinylmethyl)oxy]phenyl}-2,3,4,5-tetrahydro-1H benzazepine; 4-{[(4-methylpyridinyl)methyl]oxy}(1,2,3,4-tetrahydro isoquinolinyl)benzonitrile; 7-[2-{[(4-methylpyridinyl)methyl]oxy}(trifluoromethyl)phenyl]-1,2,3,4- ydroisoquinoline; 7-(5-(methyloxy){[(4-methylpyridinyl)methyl]oxy}phenyl)-1,2,3,4- tetrahydroisoquinoline; 7-(5-(1,1-dimethylethyl){[(4-methylpyridinyl)methyl]oxy}phenyl)-1,2,3,4- tetrahydroisoquinoline; 7-{6-methyl[(2-pyrazinylmethyl)oxy]pyridinyl}-2,3,4,5-tetrahydro-1H epine; 7-(6-methyl{[(4-methylpyridinyl)methyl]oxy}pyridinyl)-2,3,4,5-tetrahydro-1H benzazepine; 7-{5-(methyloxy)[(2-pyrazinylmethyl)oxy]phenyl}-2,3,4,5-tetrahydro-1H epine; 7-[5-(methyloxy)({[4-(methyloxy)pyridinyl]methyl}oxy)phenyl]-2,3,4,5-tetrahydro- 1Hbenzazepine; 1-[4-({[4-(methyloxy)pyridinyl]methyl}oxy)(2,3,4,5-tetrahydro-1Hbenzazepin- 7-yl)phenyl]ethanone; {[4-(methyloxy)pyridinyl]methyl}oxy)phenyl]-2,3,4,5-tetrahydro-1H benzazepine; 7-(5-fluoro{[(4-methylpyridinyl)methyl]oxy}phenyl)-2,3,4,5-tetrahydro-1H benzazepine; 7-(5-methyl{[(4-methylpyridinyl)methyl]oxy}phenyl)-2,3,4,5-tetrahydro-1H benzazepine; 7-(5-(ethyloxy){[(4-methylpyridinyl)methyl]oxy}phenyl)-2,3,4,5-tetrahydro-1H benzazepine; 7-(5-(methyloxy){[(4-methylpyridinyl)methyl]oxy}phenyl)-2,3,4,5-tetrahydro-1H- 3-benzazepine; 4-{[(4-methylpyridinyl)methyl]oxy}(2,3,4,5-tetrahydro-1Hbenzazepin yl)benzonitrile; 7-[2-{[(4-methylpyridinyl)methyl]oxy}(trifluoromethyl)phenyl]-2,3,4,5-tetrahydro- 1Hbenzazepine; 7-(5-(1,1-dimethylethyl){[(4-methylpyridinyl)methyl]oxy}phenyl)-2,3,4,5- tetrahydro-1Hbenzazepine; 7-(3-{[(4-ethylpyridinyl)methyl]oxy}methylpyridinyl)-2,3,4,5-tetrahydro-1H benzazepine; 7-(6-(1,1-dimethylethyl){[(4-methylpyridinyl)methyl]oxy}pyridinyl)-2,3,4,5- tetrahydro-1Hbenzazepine; 1-[4-{[(4-ethylpyridinyl)methyl]oxy}(2,3,4,5-tetrahydro-1Hbenzazepin yl)phenyl]ethanone; 1-[4-({[4-(ethyloxy)pyridinyl]methyl}oxy)(2,3,4,5-tetrahydro-1Hbenzazepin yl)phenyl]ethanone; 7-{5-(methyloxy)[(2-pyridinylmethyl)oxy]phenyl}-2,3,4,5-tetrahydro-1H benzazepine; 1-[4-[(2-pyridinylmethyl)oxy](1,2,3,4-tetrahydroisoquinolinyl)phenyl]ethanone; N-methyl{[(4-methylpyridinyl)methyl]oxy}(2,3,4,5-tetrahydro-1H benzazepinyl)benzamide; 4-{[(4-methylpyridinyl)methyl]oxy}(2,3,4,5-tetrahydro-1Hbenzazepin yl)benzamide; N,N-dimethyl{[(4-methylpyridinyl)methyl]oxy}(1,2,3,4-tetrahydro isoquinolinyl)benzamide; 4-{[(4-methylpyridinyl)methyl]oxy}(1,2,3,4-tetrahydroisoquinolinyl)benzamide; 7-(2,3-bis(methyloxy){[(4-methylpyridinyl)methyl]oxy}phenyl)-1,2,3,4- ydroisoquinoline; 7-(2,3-bis(methyloxy){[(4-methylpyridinyl)methyl]oxy}phenyl)-2,3,4,5-tetrahydro- enzazepine; 7-(5-chloro{[(4-methylpyridinyl)methyl]oxy}phenyl)-2,3,4,5-tetrahydro-1H benzazepine; 7-{5-chloro[(2-pyridinylmethyl)oxy]phenyl}-1,2,3,4-tetrahydroisoquinoline; 7-[6-methyl({[4-(methyloxy)pyridinyl]methyl}oxy)pyridinyl]-2,3,4,5-tetrahydro- 1Hbenzazepine; 7-(6-chloro{[(4-methylpyridinyl)methyl]oxy}pyridinyl)-2,3,4,5-tetrahydro-1H benzazepine; 7-(6-chloro{[(4-methylpyridinyl)methyl]oxy}pyridinyl)-1,2,3,4- tetrahydroisoquinoline; 1-[4-{[(4-{[2-(methyloxy)ethyl]oxy}pyridinyl)methyl]oxy}(2,3,4,5-tetrahydro-1H benzazepinyl)phenyl]ethanone; 1-{3-(2,3-dihydro-1H-isoindolyl)[(2-pyridinylmethyl)oxy]phenyl}ethanone; and 1-[4-[(2-pyridinylmethyl)oxy](1,2,3,4-tetrahydroisoquinolinyl)phenyl]ethanone; or a salt thereof.
9. A compound according to claim 1 which is selected from: 7-(3-{[(4-methylpyridinyl)methyl]oxy}pyridinyl)-2,3,4,5-tetrahydro-1H benzazepine; 7-(2-(methyloxy){[(4-methylpyridinyl)methyl]oxy}phenyl)-2,3,4,5-tetrahydro-1H- 3-benzazepine; 7-(4-(methyloxy){[(4-methylpyridinyl)methyl]oxy}phenyl)-2,3,4,5-tetrahydro-1H- 3-benzazepine; 1-[4-{[(4-methylpyridinyl)methyl]oxy}(2,3,4,5-tetrahydro-1Hbenzazepin yl)phenyl]ethanone; 1-[4-[(2-pyrazinylmethyl)oxy](2,3,4,5-tetrahydro-1Hbenzazepin nyl]ethanone; 7-(5-fluoro{[(4-methylpyridinyl)methyl]oxy}phenyl)-1,2,3,4- ydroisoquinoline; 7-[2-({[4-(methyloxy)pyridinyl]methyl}oxy)phenyl]-2,3,4,5-tetrahydro-1H benzazepine; and 1-[4-[(2-pyridinylmethyl)oxy](2,3,4,5-tetrahydro-1Hbenzazepin yl)phenyl]ethanone; or a salt f.
10. A compound according to claim I which is: 7-(2-(methyloxy){[(4-methylpyridinyl)methyl]oxy}phen 5 yl)-2,3,4,5-tetrahydro-1H- 3-benzazepine; or a salt thereof.
11. A nd according to claim 10 which is methyloxy){[(4-methyl pyridinyl)methyl]oxy}phenyl)-2,3,4,5-tetrahydro-1H- 3-benzazepine methanesulfonate.
12. A compound or a salt thereof according to any one of claims 1 to 10, wherein the salt is a pharmaceutically acceptable salt.
13. A pharmaceutical composition which comprises a compound of formula (I) or salt thereof according to any one of claims 1 to 12 and one or more ceutically acceptable carriers, ts or excipients.
14. A pharmaceutical composition according to claim 13, wherein the composition is adapted for topical dermal administration.
15. A combination comprising a compound of formula (I) or a salt thereof according to any one of claims 1 to 12, together with one or more other therapeutically active agents.
16. A compound of formula (I) or salt thereof according to any one of claims 1 to 12, for use in therapy.
17. A compound of a (I) or a salt thereof according to any one ofclaims 1 to 12, for use in inhibiting spleen tyrosine kinase.
18. A compound or a salt thereof according to any one of claims 1 to 12, for use in the ent of an autoimmune condition.
19. A compound or a salt thereof according to claim 18, wherein the autoimmune condition is chronic idiopathic urticaria with and without auto-antibody
20. The use of a compound or a salt thereof according to any one claims 1 to 12, for the manufacture of a medicament for the treatment of an autoimmune condition.
21. A compound or a salt f according to claim 1 substantially as herein described or exemplified.
22. A pharmaceutical composition according to claim 13 ntially as herein described or exemplified.
23. A combination according to claim 15 substantially as herein described or exemplified.
24. A use according to claim 20 substantially as herein described or exemplified.
NZ614199A 2011-03-11 2012-03-08 Pyridinyl- and pyrazinyl -methyloxy - aryl derivatives useful as inhibitors of spleen tyrosine kinase (syk) NZ614199B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB1104153.0 2011-03-11
GBGB1104153.0A GB201104153D0 (en) 2011-03-11 2011-03-11 Novel compounds
PCT/EP2012/053948 WO2012123311A1 (en) 2011-03-11 2012-03-08 Pyridinyl- and pyrazinyl -methyloxy - aryl derivatives useful as inhibitors of spleen tyrosine kinase (syk)

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NZ614199A NZ614199A (en) 2015-10-30
NZ614199B2 true NZ614199B2 (en) 2016-02-02

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