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 PDFInfo
- Publication number
- 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
- Authority
- NZ
- New Zealand
- Prior art keywords
- methyl
- oxy
- tetrahydro
- phenyl
- methylpyridinyl
- Prior art date
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- -1 pyrazinyl -methyloxy Chemical group 0.000 title claims abstract description 166
- 230000002401 inhibitory effect Effects 0.000 title claims abstract description 33
- 102000000551 Syk Kinase Human genes 0.000 title claims abstract description 15
- 108010016672 Syk Kinase Proteins 0.000 title claims abstract description 15
- 239000003112 inhibitor Substances 0.000 title abstract description 29
- 150000001875 compounds Chemical class 0.000 claims abstract description 186
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 137
- 230000001363 autoimmune Effects 0.000 claims abstract description 20
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 103
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- 150000003839 salts Chemical class 0.000 claims description 89
- 239000000203 mixture Substances 0.000 claims description 79
- 125000004076 pyridyl group Chemical group 0.000 claims description 67
- 239000001257 hydrogen Substances 0.000 claims description 34
- 229910052739 hydrogen Inorganic materials 0.000 claims description 34
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 28
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 26
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 16
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 16
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Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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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)
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.
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) |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ614199A NZ614199A (en) | 2015-10-30 |
NZ614199B2 true NZ614199B2 (en) | 2016-02-02 |
Family
ID=
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