CA2380775A1 - Benzoic acid derivatives and their use as ppar receptor agonists - Google Patents

Benzoic acid derivatives and their use as ppar receptor agonists Download PDF

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CA2380775A1
CA2380775A1 CA002380775A CA2380775A CA2380775A1 CA 2380775 A1 CA2380775 A1 CA 2380775A1 CA 002380775 A CA002380775 A CA 002380775A CA 2380775 A CA2380775 A CA 2380775A CA 2380775 A1 CA2380775 A1 CA 2380775A1
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optionally substituted
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hydrogen
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Paul Robert Owen Whittamore
Rodney Brian Hargreaves
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AstraZeneca AB
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    • 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
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    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
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    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4704—2-Quinolinones, e.g. carbostyril
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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
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    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
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    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract

The present invention relates to the use of certain benzoic acid derivatives of formula (I), where the substituents are as defined in the specification, which act as peroxisome proliferator activated receptor (PPAR) agonists, in particular gamma receptors (PPAR.gamma.), and so are useful in the treatment of states of insulin resistance, including type 2 diabetes mellitus.

Description

CHEMICAL COMPOUNDS
The present invention relates to the use of certain benzoic acid derivatives which act as peroxisome proliferator activated receptor (PPAR) agonists, in particular gamma receptors s (PPARy), and so are useful in the treatment of states of insulin resistance, including type 2 diabetes mellitus. Novel pharmaceutical compositions and novel compounds are also defined, together with methods of their production.
Traditionally, therapeutic intervention in type 2 diabetes has had a 'glucocentric focus' dominated by the use of insulin secretogogues e.g. the sulphonylureas and the measurement of 1o glycated haemoglobin (HbAlc) or fasting blood sugar level (FPG) as indices of diabetic control.
In the USA, patients with type 2 diabetes are usually treated with diet and, when needed, a sulphonylurea compound. However, it is estimated that approximately 30% of patients initially treated with sulphonylurea agents have a poor response and in the remaining 70%, the subsequent failure rate is approximately 4-5% per annum. Other estimates put failure rates higher 15 with few patients responding after 10 years therapy. A treatment-related increase in body weight is also experienced with these agents. Prior to the FDA approval of metformin in 1995, the only therapeutic option for type 2 diabetic patients, in whom sulphonylurea therapy had failed, was insulin.
Despite the introduction of newer agents both the incidence and prevalence of type 2 2o diabetes continues to increase on a global basis. Approximately 16 million people in the USA
have diabetes mellitus, 90-95% of whom have type 2 disease. This represents an enormous healthcare burden; estimated in 1998 to be some $98 billion per annum in direct and indirect healthcare costs. Recently, both the ADA and WHO have revised guidelines for the diagnosis of diabetes and classified diabetes more according to aetiology. The threshold for diagnosis (FPG >
25 126mg/dl) has been lowered and the term 'type 2' is now used to describe mature onset diabetics who have not progressed to insulin therapy. After the ADA implemented these new criteria in 1997, the prevalence of the type 2 disease sector increased by nearly 6 million people in the seven major pharmaceutical markets (France, Germany, Italy, Japan, Spain, UK
and USA).
Apart from often mild acute symptoms, type 2 diabetics are also at a considerable risk of 3o developing long term complications of the disease. These include a 4-5 fold higher risk, (compared with non-diabetics), of developing macrovasular disease including CHD and PVD
and microvascular complications including retinopathy, nephropathy and neuropathy. In many individuals, overt type 2 diabetes is preceded by a period of reduced insulin sensitivity (insulin resistance), accompanied by a cluster of other cardiovascular risk factors, collectively termed as insulin resistance syndrome (IRS).
It has been estimated that approximately 80% of type 2 diabetics are obese and other co morbidities of the IRS include: dyslipidemia, hyperinsulinemia, raised arterial blood pressure, uricemia and a reduced fibrinolysis. Given the increased global prevalence and incidence of type 2 diabetes and the very high costs of treating the long term complications of the disease there is tremendous interest in the development of agents that delay or prevent the onset of type 2 diabetes and in those that reduce the risk of cardiovascular complications associated with IRS.
These activities have lead to the introduction of the thiazolidinedione (TZD) class of insulin to sensitisers that improved the dyslipidemia and thus restored the insulin sensitivity leading to improved glycemic control and lower HbAlc levels.
Although the complex interplay between lipids and carbohydrates as metabolic fuels has been recognised for many decades it is only recently, that researchers and clinicians have begun to focus on the importance of dyslipidemia seen in type 2 diabetes. Much has been made of the relative sensitivities of muscle, liver and adipose tissues to insulin and a case for the primacy of insulin resistance in adipose tissue leading to the IRS has been debated. A
typical dyslipidemic atherogenic lipoprotein phenotype (referred to as type B) is seen in IRS
including frequently in type 2 diabetics, characterised by a modestly raised LDL-C, a more significant increase in VLDL-TG and reduced HDL. Apparently, changes in the physicochemical properties of VLDL-2o TG particles result in slower plasma clearance rates and in the generation of small dense LDL
particles. The latter permeate the vascular endothelium more readily and are more prone to oxidation and glycation and are considered to play a critical role in atherogenesis in large vessels.
Although more difficult to measure, improved free fatty acid (IFFA) flux is increasingly considered to play an important role in the IRS affecting metabolic events in muscle, liver, adipose tissue and pancreas.
The first generation TZDs e.g. troglitazone, pioglitazone, rosiglitazone were in clinical development before the putative mechanism of action was discovered and published in 1995 (PPARy activation). It is clear from experience with these first generation agents that it is difficult to predict from animal pharmacology the safety and efficacy profile these agents will 3o have in the clinic. Thus, knowledge of the putative mechanism of action of this class coupled with concerns regarding safety, offers the opportunity to identify non-TZD
activators of PPAR
for the treatment of type 2 diabetes and is the subject of this invention.
Furthermore, we recognise that agents with a dual action at both a and g PPAR may have additional benefits in reducing diabetic co-morbidities, particularly raised triglycerides. Such agents may be useful in the treatment of type 2 diabetes, the IRS, dyslipidemia and in reducing risk of cardiovascular disease.
US Patent No 5151435 and EP-A-S 17357 describe the use of certain indole derivatives as angiotensin II antagonists. W09808818 describes the use of inter alia other indole derivatives as phospholipase inhibitors. Tetrahydroisoquinoline derivatives useful as thromboxane A2 antagonists are described in EP-A-300725.
The present invention provides the use of a compound of formula (I) \ Y~z R? (Q)1 I
(R3)m I (R')n to COOH (n or a pharmaceutically acceptable salt or ester thereof, in the preparation of a medicament for use in the activation of PPAR, X, Y and Z may represent either bonds or atoms or groups of atoms such that X, Y and Z
together with the nitrogen atom complete an optionally substituted five or six-membered aromatic or non-aromatic nng;
where each R' is selected from C1_3alkyl, halo, haloCl_3alkyl, C1_3alkoxy, optionally substituted hydrocarbyl or optionally substituted heterocyclyl and n is 0, 1 or 2;
Rz is selected from R4, OQR4, C(O)pR4, S(O)qR4, N(QR6) R', halo, cyano, carboxy, nitro, (O)CN(QR6) R', OC(O)N(QR6) R', NRSC(O)pRb, NRSCON(QR6) R', NRSCSN(QR6) R', 2o NRSC(O)OR6, N=CR6R', S(O)qN(QR6) R' or NRSS(O)qRb, or RZ is carboxy, CH=CHQR4 or ~SC(~)C(~)Rbo where p is 1 or 2, q is 0, 1, 2 or 3;
R4 is selected from optionally substituted hydrocarbyl or optionally substituted Qheterocyclyl groups;
R', R6 and R' are independently selected from hydrogen, optionally substituted hydrocarbyl or optionally substituted Qheterocyclyl groups or R6 and R' together with the atom to which they are attached form a ring which may be optionally substituted and which may comprise one or more heteroatoms;
lis0orl;
each Q is independantly selected from a direct bond, C1_3alkylene or C2_3alkenylene;
each R3 is independently selected from Ct_3alkyl, halo, haloC~_3alkyl, C1_3alkoxy and m is 0, 1 or 2.
As used herein, the term "hydrocarbyl" refers to alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkenyl or cycloalkynyl groups.
The term "heterocyclyl" refers to single or fused ring structures which, unless stated otherwise, may be aromatic or non-aromatic in nature and which suitably contain from 2 to 20 ring atoms, suitably from 5 to 8 ring atoms, at least one of which and suitably up to four of which are heteroatoms. The term "heteroatom" includes oxygen, sulphur and nitrogen. Where a 1o heteroatom is nitrogen, it will be further substituted for example by hydrogen or an alkyl group.
Examples of such groups include furyl, thienyl, pyrrolyl, pyrrolidinyl, imidazolyl, triazolyl, thiazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, benzothiazolyl, benzoxazolyl, benzothienyl or benzofuryl.
"Heteroaryl" refers to those groups described above which have an aromatic character.
In this specification the term "aryl" refers to phenyl, biphenyl and naphthyl.
In this specification the term "alkyl" when used either alone or as a suffix includes straight chained, branched structures. These groups may contain up to 10, preferably up to 6 and more preferably up to 4 carbon atoms. Similarly the terms "alkenyl" and "alkynyl" refer to 2o unsaturated straight or branched structures containing for example from 2 to 10, preferably from 2 to 6 carbon atoms. Cyclic moieties such as cycloalkyl, cycloalkenyl and cycloalkynyl are similar in nature but have at least 3 carbon atoms, suitably from 3 to 20 carbon atoms and preferably from 3 to 7 carbon atoms. Terms such as "alkoxy" and "thioalkyl"
comprise alkyl groups as is understood in the art.
The term "halo" includes fluoro, chloro, bromo and iodo. References to aryl groups include aromatic carbocylic groups such as phenyl and naphthyl. The term "aralkyl" refers to alkyl groups substituted with aryl, such as benzyl.
Preferably 1 is 1.
Preferably n is 0 or 1. Ideally n is 0.
3o Preferably m is 0 or 1. Ideally m is 0.
Preferably Rl is selected from C~_3alkyl, halo, haloC~_3alkyl and C1_3alkoxy.
Suitably in the compounds of formula (I), X is a bond or a group CHZ or C(O);
and -Y-Z-is selected from -CRI'=CRIB-, -C(O)- CRI'=CRIB-, -CR' OCR'~ 8C(0)-, -CHR' ~-CHR' g-C(O)-, -CHR' ~-CHR' 8-CHR' 9-, where R' ~, R' g and R' 9 are independently selected from hydrogen or C1_3 alkyl such as methyl. Thus, in formula (I), the Group of sub formula (a) \ Y~z Ri (Q)I I
/ X~N-.
(R3)m s (a) is suitably selected from a group of sub-formula (b), (c), (d), (e), (f), (g), (h) or (i).
O
\ R~~ Rya \ Ris R2 (Q~ / ~ R2 (O Rz_(Q~ /
(R3) i R~s ~K,,~m ( ~ (R3)m i O
(c) R~~
R~$ \ \ Rya Ris R2 (Q R? (Q~ / ~ R? (Q~ \
/ N
~K~'~m I R~9 (R3)m (R3)m (e) O
R» (f) R~~ (9) \ \
R? ((~~ / ~>--Ria R? (Q~ / ~R~s (R3)m ' ~ (R3)m (h) (i) where R2, Q, 1, R3 and m are as defined in relation to formula (I).
R", R'8 and R'9 are selected from hydrogen and C1_Salkyl. Preferably R", R'8 and R'9 to are all hydrogen.
Preferably compounds of formula (I) are indoles of formula (II) R? (Q \
/ N~
(R3)m w (R1)~
COOH
Wherein A, R1, R2, R3, m and n are as defined above.
The carboxyl group of formula (I) is suitably at the ortho position on the phenyl ring.
Thus in the case of the indoles, a particular preferred group of compounds are those of formula R2 (Q~ /
~R3~m w R1 HOOC
Where present, in the compound of formula (I), (II) or (IIA) Rl and R3 are suitably to independently selected from halo, methyl and trifluoromethyl, and are preferably halo. Most preferably however, n and m are 0.
Suitable optional substitutents for the heterocyclyl group include carboxyalkyl or carboxyalkenyl.
Thus a particularly preferred group of compounds of formula (IIA) are compounds of formula (III) R? (Q
~R3~m where A and RZ are as defined above.
2o Suitable optional substituents on the five or six membered aromatic or non-aromatic ring formed by X, Y and Z are C~_5alkyl, halo, haloC,_Salkyl, =O, hydroxy, carboxy and C»alkoxy.
Preferably X, Y and Z are unsubstututed or substituted by Cl_Salkyl.
Suitable optional substitutents for any hydrocarbyl groups within R', R'~, R5, R6 and R7 include halo, cyano, nitro, C(O)aRg, ORB, S(O)bRB, NR9R~°, C(O)NR9R1°, OC(O)NR9R~°, NRgC(O)aR9, NR$CONR9R~°, N=CR9R1°, S(O)bNR9Rlo or NRBS(O)bRlo where Rg , R9 and Rlo HOOC
are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkoxy, aralkyl, cycloalkyl, cycloalkenyl or cycloalkynyl, any of which may themselves be optionally substituted, a is 1 or 2 and b is 0, 1, 2 or 3.
Suitable optional substitutents for any heterocyclyl groups within R', R4, R5, R6 and R' include those listed above for hydrocarbyl groups, as well as alkyl, alkenyl or alkynyl groups which may be optionally substituted, for example with halo, cyano, vitro, C(O)aR", ORl', S(O)bRy yzRis~ C(O)~nRiz~ OC(O)NR'ZRi3~ ~nC(O)aR~2~ ~aCONR'zRi3~
N=CR'ZR'3, S(O)bNR'ZR'3 or NR"S(O)bR'Z where R" , R'2 and R'3 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkoxy, aralkyl, cycloalkyl, to cycloalkenyl or cycloalkynyl, and a and b are as defined above.
Suitable optional substituents for alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkoxy, aralkyl, cycloalkyl, cycloalkenyl or cycloalkynyl groups within Rg , R9 and R'° include halo, vitro cyano, alkanoyl such as acetyl, oxo, carboxy or salts or esters thereof, alkoxy such as methoxy, ethoxy or propoxy, aryloxy such as phenoxy, thioalkyl such as thiomethyl, thioethyl or ~5 thiopropyl, sulphate, haloalkyl such as trifluoromethyl, aryl such as phenyl, carbamate, amino, mono- or di-alkyl amino such as methylamino or di-methylamino. Aryl, heterocyclyl or aralkyl groups Rg , R9 and R'° may further be substituted by alkyl, alkenyl or alkynyl groups suitably having from 1 to 4 carbon atoms.
The group Rz is preferably selected from R4, OQR4, C(O)pR4, NR6R~, vitro, 20 C(O)NR6R', OC(O)N(QR6)R~, NRSC(O)nR6, NRSCON(QR6)R~, NRSCSN(QR6)R~, NRSC(O)OR6 where Q, R'~, R5, R6 and R' are as defined above.
Preferably Rz is selected from R4, OQR'', NR6R' and C(O)NR6R~ where Q, R4, R5, and R' are as defined above.
A particularly preferred group RZ is OR4. In this case R4 is suitably substituted alkyl, in 25 particular substituted methyl, heterocyclyl or carbocyclyl. In particular, R4 is substituted alkyl where the substitutent on the alkyl group is aryl in particular phenyl, which may itself be optionally substituted with one or more groups selected from alkyl such as C,_3 alkyl, halo such as chloro, alkylsulphonyl such as methylsulphonyl, alkoxy such as methoxy, aryl such as phenyl or aryloxy such as phenoxy.
3o A further preferred group RZ is a group NRSC(O)OR6 where RS is hydrogen and R6 is alkyl, in particular C1_6 alkyl, such as butyl or tert-butyl.
Particular examples of compounds of formula (I) are listed in Tables 1- 3 below.

_g_ R2a OOH
Table 1 No R ~ R R R
1 ~ H H H
N /
O
~*
2 H ~ ~ H H
N ~*
3 H H ~ ~ H
N *
4 H ~ ~ H H
*
H ~ H H
~*
N N
6 H w H H
\~o~~
7 H ( w H H
i 8 H I ~ * H H
o' 9 H 0~ H H
~N
~*
H H02C~0\* H H

12 H 0~ H H
~N
~*
13 H y ~ H H
\ ,N
H
14 H \ Di* H H
I
C
H ~ \ H H
~*
/ O
16 H ~ ~ Ci H H
17 H N * H H
18 H I ~ ° I ~ °~~ H H
i i 19 H I ~ o~* H H
i H ~ o~* H H
i ~s \o 21 H o H H
~o \ o~.
o I /
22 H I \ N~= H H
H
\ /
/
23 H I ~ H H
/ N N\*
24 H ~ H H
N N\.
25 H N * H H
\ ~ \
26 H CH3(CHZ)3NHC(O)- H H
27 H \ I ~ H H
N
28 H ° H H
~N
II H
O~~
29 H / \ ~ H H
N
S H
30 H H I ~ \ H
/
N
31 ~ w ~ H H H
CI ~ N
0~
32 H ( ~ o~= H H
F
33 H ~ H H H
O N~*
34 H ° H H H
N~.
/ a I/
35 H F ~ H H
36 H ° H H
N
Nr " H
OZ
37 H ~ H H
H H~
38 H ~ H H
~.
H H
39 H ~ H H
Hue.

N- \' H
41 H ° H H
N
n~ H
rr ~~''/

42 H HOzC / H H
43 H ° H H
~I
44 H ~ ~ ° H H
s N /I
H
45 H /~ ° H H
' N / I
O,NJ \
I/
46 H , I H CH3 i o~
47 H , , H CH3 \N~p\*
48 H \ I ~' H H
N
H
49 H CppH H H
50 H \ I ~* H H
N
H
51 H \ SpN \* H H
z 52 H ° H H
\ N~.
H
\ /
I
53 H H * H H
song/
i N~
O
SS H ~ H H

56 H ° ~ H H
\ ~NH N~.
/ H
57 H ° H H
N~p~.
~H

o~
I N
H
F /
59 H \ I H H
N \
H
60 H I \ H H
\ o~
N
H
61 H ~ H H
I
\ ~ \ I N~y l~H
62 H \ I H H
N \
H
63 H ~ H H
N
H
\O ~ /
64 H a \ H H
I / N
O\=
65 H I ~ ~ o/ ~ H H
/ N O
66 H o / I H H
w N/ \ ow.
67 H I w w o/* H H
N
68 H ~ ~ o/* H H
~N
69 H F I \ \ °i H H
~N O
70 H N~N N H H

71 H ~ H H
H
72 H °u H H
\ N~' H
\O I /
73 H ° H H
\ N~' '~ H
CI' v 74 H °I ~, H H
I \ N
H
75 H I ° H H
\ N~.
H
76 H -° ° H H
~\ N~.
II H
~/
77 H \ I ~= H H
N
H
78 H -° ° H H
\ N~' /~ H
-O
79 H ° H H
\ N
H

80 H ~° H H
\ \ N' \' H
/ /
81 H ~f H H
\ ~N
H
.N I /
N, S
82 H F ° H H
\ N
~H
83 H ~° I \ ~ ~ H H
O / N
H
84 H ~ ~ H H
N
H

\ /
H
\ I N~.
O
R / Y ~z~
t ,.
N~Z COOH

Table 2 No R2' Y' Z' Z"

100 ~ ~ CHZ CHZ CHz N

101 ~ ~ CH CH C(O) N

102 ~ ~ CHZ CHZ C(O) N

The use of certain compounds of formula (I) in any medical application has not been described before. Hence, in a further aspect the invention provides the use of these particular compounds as medicaments, and pharmaceutical compositions containing them.
Thus the invention provides compounds of formula (IA) which comprises a compound of formula (I) as defined above, where X is a bond or a group CHZ or C(O); and -Y-Z- is selected to from is selected from -CR'7=CRlB-, -C(O)- CR'~=CR'8-, -CR'~=CR'gC(O)-, -CHR'~-CHRIS-C(O)-, -CHRI~-CHR'8-CHR'9-, where R'7, R'8 and R'9 are independently selected from hydrogen or C1_3 alkyl such as methyl; provided that (i) where the group of sub-formula (a) as defined above is a group of sub-formula (h) and R" and R'$ are hydrogen, Rz is other than (2-ethyl-5,7-dimethyl-3H imidazo [4,5-b]pyridin-3-yl)methyl, or methyl substituted with an aromatic heterocyclic ring containing 2 or 3 nitrogen atoms;
(ii) where the group of sub-formula (a) as defined above is a group of sub-formula (g) as defined above and R" and R'8 are hydrogen, RZ is other than a group S(O)qNR6R~ where q is 2, R6 is hydrogen and R' is 2-chlorophenyl; or (iii) where the group of sub-formula (a) is a group of sub-formula (i) as defined above and RI' 2o and R'g are hydrogen, either Rz is other than halo, cyano, nitro, C~_salkyl, CZ_salkenyl, Cz_salkynyl, optionally substituted phenyl or a group OR'4, NR1~R's or SR''~
where R'4 and Rls are selected from hydrogen, C,_salkyl, Cz_salkenyl or Cz_salkynyl or optionally substituted phenyl, or m is other than 0.
for use as a medicament, in particular for the activation of PPARy and in the treatment of diabetes.
In addition, the invention provides a pharmaceutical composition comprising a compound of formula (IA) in combination with a pharmaceutically acceptable carrier.
Compounds of formula (IA) as defined above are novel and form a further aspect of the invention.
Preferred groups and moieties which are present in the compounds of formula (IA) are those preferred groups defined above in relation to formula (I).
Compounds of formula (I) are either known compounds or they may be prepared using to conventional methods. In particular however, compounds of formula (I) may be prepared by reacting a compound of formula (III) Y~
R31 _ R32 Z
/ ,N
~R3)m X ~ \R1)f1 COOR3o with a compound of formula (IV) R3a_R33 (IV) where X, Y, Z, R3, Rl, n and m are as defined in relation to formula (I), R3o is an ester protecting group, in particular an alkyl group, one of R31 or R33 is a leaving group and the other is hydrogen or a group which reacts with and eliminates said leaving group, R3z is a bond or is a precursor to R2, and R34 is a group RZ as defined in relation to formula (I) or a part thereof, such that where R34-R32 forms a group R2;
and thereafter if necessary or desired carrying out one or more of the following steps:
(i) removing a protecting group R3°:
(ii) converting a group RZ to a different such group.
Suitable leaving groups for R3' or R33 include halogen, such as bromine, mesylate or tosylate. Other examples of leaving groups may comprise hydroxy, where for example this 3o forms part of an acid group (e.g. in the case of R3', where R32 comprises a carbonyl group) which may be condensed, for example with amines of formula (IV) to form compounds where Rz is an amide group. The other may comprise hydrogen, but other reactive groups such as boronic acid, which would react with and eliminate halo groups may also be employed. The reaction is suitably effected in a solvent such as an organic solvent and or water, in the presence of a base such as an alkali metal carbonate such as potassium carbonate. Catalysts such as palladium catalysts and elevated temperatures for example at the reflux temperature of the solvent, may be employed to assist the reaction.
Examples of groups R3z include functional type derivatives such as secondary amine groups -NR6-, -O-, C(O), S(O)q, C(O)NR6, OC(O)NR6, NRSC(O)~, NRSCONR6, NRSCSNR6, 1o NRSC(O)O, N=CR6, S(O)qNRbor NRSS(O)q where p, q and RS and R6 are as defined above.
Terminal groups such as R4 and R' will then comprise the moiety R34 above.
Examples of such reactions are illustrated hereinafter. Suitable combinations of compounds of formula (>~ and (IV) can be summarised are illustrated in Table 3 Table 3 IV
\ Y~z R'-H
hal I
,N
(R3)m X ( \ (R~)n COOR3o \ Y~
z H / ~N R4-hal (Rs) X ( \ (R~)n m /
COOR3o \Y\z. R'-hal RsH N I
/ ~N where hal is a halogen atom such as X \
(R3)m ~ / (R~)" bromine or chlorine COOR3o \ Y~Z R3'~-hal HR3z I
~ XiIV \
(R3)m ~ / ~R~~" where hal is a halogen atom such as COOR3o bromine or chlorine Deprotection to remove the group R3° can be carried out by conventional methods, for example by acidifying the compound using a mineral acid such as hydrochloric acid.
Optional step (ii) above can be carried out using various methods depending upon the nature of the Rz groups involved and could be derived from the literature.
Compounds of formula (III) may be prepared by reacting a compound of formula (V) Y~
Rs~_Rsz I
X~N~H
(R3~m (V) where X, Y, Z, R3, and m are as defined in relation to formula (I), and R3 ~
and R32 are as defined in relation to formula (III), with a compound of formula (VI) ~R~~n COOR3o (VI) where R1 and n are as defined in relation to formula (I), R3° is as defined in relation to formula (III) and R36 is a leaving group.
Suitable leaving groups for R36 include those listed above for R3' or R33 and in particular is halo such as bromo. The reaction is suitably effected in an organic solvent such as butanone or ?0 dimethylformamide (DMF), in the presence of a base such as an alkali metal carbonate, for example potassium carbonate or an alkali metal hydride such as sodium hydride.
Elevated temperatures, for example the reflux temperature of the solvent may be employed.
Alternatively, compounds of formula (I) may be prepared by reacting a compound of formula (VII) \ Y~z R? (Q)1 I
/
(R3)m (VII) where X, Y, Z, Rz, R3 and m are as defined in relation to formula (I), with a compound of formula (VI) as defined above, and thereafter if necessary or desired, carrying out optional steps (i) and (ii) above. Suitable reaction conditions will be similar to those described for the reaction between compound of formula (V) and (VI).
Compounds of formula (VII) may be prepared by reacting a compound of formula (VIII) / Y~z X~ N-H
(R3)m (VIII) where X, Y, Z, R3 and m are as defined in relation to formula (I) and R31 is as defined in relation to formula (III), which a compound of formula (IV) as defined above. Suitable reaction t5 conditions include those listed above for the reaction between compounds of formula (III) and (N).
Compounds of formulae (IV), (V), (VI] and (VIII) are either known compounds or they can be prepared from known compounds by conventional methods. Compounds of formula (V) where R3I-R3z is a complex moiety may be constructed in stages as would be understood by a 2o chemist, and examples of such procedures are given hereinafter.
The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a 25 finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).
The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc;
preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as 1o ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal track, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.
Compositions for oral use may be in the form of hard gelatin capsules in which the active 15 ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, 2o methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxyethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters 25 derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol 3o anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). The oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or acetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and 1o suspending agents are exemplified by those already mentioned above.
Additional excipients such as sweetening, flavouring and colouring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these. Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as Soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavouring and preservative agents.
2o Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent.
The pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above. A sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol.
Suppository formulations may be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
Suitable excipients include, for example, cocoa butter and polyethylene glycols.
Topical formulations, such as creams, ointments, gels and aqueous or oily solutions or suspensions, may generally be obtained by formulating an active ingredient with a conventional, topically acceptable, vehicle or diluent using conventional procedure well known in the art.
Compositions for administration by insufflation may be in the form of a finely divided powder containing particles of average diameter of, for example, 30~ or much less, the powder itself comprising either active ingredient alone or diluted with one or more physiologically acceptable carriers such as lactose. The powder for insufflation is then conveniently retained in a capsule containing, for example, 1 to SOmg of active ingredient for use with a turbo-inhaler device, such as is used for insufflation of the known agent sodium cromoglycate.
1o Compositions for administration by inhalation may be in the form of a conventional pressurised aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient.
For further information on Formulation the reader is referred to Chapter 25.2 in Volume ~
of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.
The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition. Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient. For further information on Routes of Administration and Dosage Regimes the reader is referred to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.
The size of the dose for therapeutic or prophylactic purposes of a compound of the Formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine. In particular, compounds of formula (I) and compositions containing them will be used in the treatment of diabetes.
Thus in yet a further aspect, the invention provides a method of treating diabetes which comprises administering to a patient an effective amount of a compound of formula (n as defined above.
The invention will now be particularly described by way of example.
EXAMPLES
Example 1 Preparation of Compound 42 in Table 1 Step 1 Preparation of 5-Bromo-1-(2-carboethoxybenzyl)indole to Br I~
N
COzEt A mixture of 5-bromoindole (11.36 g, 58 mmol), ethyl 2-bromomethylbenzoate (73% pure, 23.4 g, 70 mmol) and powdered potassium carbonate (40 g, 0.29 mol) in 2-butanone (265 ml) was stired under reflux for 40 hr. The cooled reaction mixture was filtered and the filter cake was washed well with 2-butanone. The filtrate was evaporated to dryness and the residue was dissolved in ethyl acetate. This solution was washed with water, dried and evaporated. The crude product was chromatographed on Kieselgel 60, eluting with a gradient of 0-5% v/v ethyl acetate in isohexane. Fractions containing the required product by tlc were pooled, evaporated 2o and the product was rechromatographed, eluting with a gradient of 10-25%
v/v dichloromethane in isohexane. There was thus obtained 5-Bromo-1-(2-carboethoxybenzyl)indole (5.82 g) as an oil: NMR d (db-DMSO) 1.33 (3 H, t), 4.33 (4 H, q), 5.77 (2 H, s), 6.43 (1H, d), 6.52 (1 H, d), 7.17 (1 H, d), 7.28 (1 H, d), 7.39 (2 H, m), 7.47 (1 H, d), 7.76 (1 H, s), 7.92 (1 H, d); MS [MH]+
358/360.
Step 2 Preparation of 1-(2-Carboethoxybenzyl)-5-(4-carboxyphenyl)indole HOZC /
N
/ COZEt A mixture of 5-bromo-1-(2-carboethoxybenzyl)indole (260 mg, 0.73 mmol) from Step 1, 4-carboxybenzeneboronic acid (145 mg, 0.87 mmol), potassium carbonate (361 mg, 2.6 mmol) and dichlorobis[tri(o-tolyl)phosphine]palladium(II) (17 mg, 0.02 mmol) in 1,2-dimethoxyethane (10 ml) and water (5 ml) was stirred for 1 hr at 100°C. The cooled reaction mixture was acidified with 2M hydrochloric acid to pH 1 and extracted with ethyl acetate. The ethyl acetate solution was washed with brine, dried and evaporated. The crude product was purified by chromatography on a l Og IsoluteT"" silica column, eluting with dichloromethane followed by 0.5% v/v ethanol in dichloromethane. There was thus obtained 1-(2-carboethoxybenzyl)-5-(4-carboxyphenyl)indole (144 mg): NMR d (db-DMSO) 1.33 (3 H, t), 4.33 (4 H, q), 5.80 (2 H, s), 6.49 ( 1 H, d), 6.61 ( 1 H, d), 7.43 (5 H, m), 7.79 (2 H, d), 7.96 (4 H, m);
MS [MH]+ 400.
Step 3 (1-(2-Carboxybenzyl)-5-(4-carboxyphenyl)indole) (Compound 42) A mixture of 1-(2-carboethoxybenzyl)-5-(4-carboxyphenyl)indole (111 mg, 0.28 mmol) and 1M
aqueous lithium hydroxide (830 ~,1, 0.83 mmol) in ethanol (10 ml) was stirred for 16 hr under reflux. A further portion of 1 M lithium hydroxide (8.3 ml, 83 mmol) was added and stirnng under reflux was continued for 3 hr, when tlc indicated that complete hydrolysis had occurred.
2o The ethanol was evaporated and the aqueous residue was acidified with 2M
hydrochloric acid to pH 1. The precipitated solid was filtered off, washed with water, vacuum dried and chromatographed on a 10 g IsoluteT"~ silica column (supplied commercially by International Sorbent Technology), eluting with a gradient of 0-10% v/v methanol in dichloromethane. There was thus obtained 1-(2-Carboxybenzyl)-5-(4-carboxyphenyl)indole (54 mg): NMR d (d6-DMSO) 5.90 (2 H, s), 6.54 (1 H, d), 6.68 (1 H, d), 7.48 (S H, m), 7.85 (2 H, d), 8.03 (4 H, m);
MS [MH]+ 372.
Example 2 Preparation of Compound 35 in Table 1 ( 1-(2-Carboxybenzyl)-5-(4-fluorophenyl)indole) F /
N
/ COZH
By the method of Example 1 and using 4-fluorobenzeneboronic acid in place of 4-carboxybenzeneboronic acid, the starting material 5-bromo-1-(2-carboethoxybenzyl)indole was converted into 1-(2-carboxybenzyl)-S-(4-fluorophenyl)indole: NMR d (db-DMSO) 5.83 (2 H, s), 6.48 ( 1 H, d), 6. S 6 ( 1 H, d), 7.31 (6 H, m), 7.48 ( 1 H, d), 7.65 (2 H, m), 7.80 ( 1 H, s), 7.92 ( 1 H, 1o m); MS [MH]+346.
Example 3 Preparation of compound 15 in Table 1 1-(2-Carboxybenzyl)-5-(2-benzofuranyl)indole By the method of Example 1 and using benzofuran-2-boronic acid in place of 4-carboxybenzeneboronic acid, the starting material 5-bromo-1-(2-carboethoxybenzyl)indole was converted into 1-(2-carboxybenzyl)-S-(2-benzofuranyl)indole: NMR d (db-DMSO) 5.83 (2H, s), 6.48 ( 1 H, d), 6.63 ( 1 H, d), 7.43 ( 1 OH, m), 7.93 ( 1 H, d), 8.16 ( 1 H, s); MS [MH]+ 368.
2o Example 4 Preparation of Compound 43 in Table 1 Step 1 Preparation of 5-(N Butylcarboxamido)-1-(2-carboethoxybenzyl)indole ~N
H
OzEt A mixture of 1-(2-carboethoxybenzyl)-5-(4-carboxyphenyl)indole (250 mg, 0.63 mmol) (Example 1 Step 2), n-butylamine (68 p1, 0.69 mmol), 1-hydroxybenzotriazole hydrate (105 mg, 0.69 mmol), N-methylmorpholine (76 ~1, 0.69 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (132 mg, 0.69 mmol) in NN-dimethylformamide (10 ml) was stirred for 16 hr to give a clear solution. The solvent was evaporated and the residue was dissolved in dichloromethane (10 ml). This solution was washed sequentially with water, 1M
aqueous citric acid, aqueous sodium bicarbonate and brine. The dried organic phase was 1o evaporated to give 5-(N butylcarboxamido)-1-(2-carboethoxybenzyl)indole (209 mg) as an orange gum: NMR d (db-DMSO) 0.89 (3 H, m), 1.33 (5 H, m), 1.51 (2 H, m), 3.27 (2 H, m), 4.36 (2 H, q), 5.80 (2 H, s), 6.49 (1 H, d), 6.60 (1 H, d), 7.41 (5 H, m), 7.73 (2 H, d), 7.91 (4 H
,m), 8.39 (1 H, t); MS [MH]+ 455.
Step 2 5-(N Butylcarboxamido)-1-(2-carboxybenzyl)indole (Compound 43) A mixture of 5-(N butylcarboxamido)-1-(2-carboethoxybenzyl)indole (176 mg, 0.39 mmol) and 1M aqueous lithium hydroxide (3.9 ml, 3.9 mmol) in ethanol (10 ml) was stirred for 60 hr to give a clear solution. The reaction mixture was evaporated to dryness and the residue was partitioned 2o between dichloromethane (10 ml), methanol (1 ml) and water (5 ml) with acidification of the aqueous layer to pH 1 with 1M hydrochloric acid. The organic layer was filtered and evaporated to dyness to yield 5-(N butylcarboxamido)-1-(2-carboxybenzyl)indole (111 mg) as a yellow solid: NMR d (db-DMSO) 0.89 (3 H, m), 1.33 (2 H, m), 1.51 (2 H, m), 3.27 (2 H, m), 5.83 (2 H, s), 6.47 (1 H, d), 6.60 (1 H, d), 7.41 (5 H, m), 7.84 (6 H, m), 8.39 (1 H, t);
MS [MH]+ 427.
Example 5 Preparation of Compound 44 in Table 1 1-(2-Carboxybenzyl)-5-{N [2-(2-thienyl)ethyl]carboxamido}indole By the method of Example 4 and using 2-(2-thienyl)ethylamine in place of n-butylamine, the starting material 1-(2-carboethoxybenzyl)-5-(4-carboxyphenyl)indole was converted into 1-(2-carboxybenzyl)-5-{N [2-(2-thienyl)ethyl]carboxamido}indole: NMR d (d6-DMSO) 3.07 (2 H, m), 3.51 (2 H, m), 5.83 (2 H, s), 6.48 (1 H, d), 6.60 (1 H, d), 6.93 (2 H, m), 7.40 (6 H, m), 7.83 (6 H, m), 8.60 (1 H, t); MS [MH]+ 481.
to Example 6 Preparation of Compound 45 in Table 1 1-(2-Carboxybenzyl)-5- { [(4-phenylpiperazino)carbonyl]phenyl} indole By the method of Example 4 and using 4-phenylpiperazine in place of n-butylamine, the starting material 1-(2-carboethoxybenzyl)-5-(4-carboxyphenyl)indole was converted into 1-(2-carboxybenzyl)-5-{[(4-phenylpiperazino)carbonyl]phenyl}indo1e: NMR d (d6-DMSO) 3.14 (4 H, m), 3.65 (4 H, m), 5.83 (2 H, s), 6.49 (1 H, d), 6.60 (1 H, d), 6.80 (1 H, t), 6.94 (2 H, m), 7.21 (2 H, t), 7.43 (7 H, m), 7.73 (2 H, d), 7.93 (2 H, m); MS [MH]+ S 16.
2o Example 7 Preparation of Compound 47 in Table 1 Step 1 5-Benzyloxy-3-methylindole \ ~ O \
N
H
A solution of 5-benzyloxyindole-3-carboxaldehyde (3.78 g, 15.1 mmol) in anhydrous tetrahydrofuran (70 ml) was stirred during the dropwise addition of a I.OM
solution of lithium aluminium hydride in tetrahydrofuran (30 ml) at such a rate as to cause the solution to reflux 3o gently. Stirnng was continued for 3 hr whilst the solution cooled to ambient temperature. Ethyl acetate (10 ml) was cautiously added follows by water (50 ml). The mixture was filtered through celite and the filter cake was washed well with ether. The filtrates were extracted with ether.
The ether extracts were dried and evaporated to a brown gum which was chromatographed on Kieselgel 60 (ART 9385, Merck, Darmstadt) eluting with 40% v/v dichloromethane in isohexane. There was thus obtained the title compound (2.05 g): NMR ~ (CDC13) 2.30 (3 H, s), 5.13 (3 H, s), 6.92 ( 1 H, dd), 6.93 ( 1 H, s), 7.13 ( 1 H, d), 7.24 ( 1 H, d), 7.30 (3 H, m), 7.47 ( 1 H, s), 7.50 (1 H, d), 7.75 (1 H, broad); MS [MH]+ 238.
Step 2 5-Benzyloxy-2-(2-carboethoxybenzyl)-3-methylindole 1o N
COZEt Sodium hydride (367 mg of a 60% dispersion in mineral oil, (9.2 mmol) was added in portions to a stirred solution of 5-Benzyloxy-3-methylindole (1.98 g, 8.35 mmol) in anhydrous N,N-dimethylformamide (30 ml). Stirring was continued for 30 min then a solution of ethyl 2-bromomethylbenzoate (2.54 g, 10.4 mmol) in N,N-dimethylformamide (5 ml) was added and the mixture was stirred for 16 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried and evaporated to a gum which was purified by chromatography on Kieselgel 60, eluting with 40%v/v dichloromethane in isohexane 2o to yield the title compound as a pale golden gum (2.24 g): NMR 8 (CDCl3) 1.42 (3 H, t), 2.54 (3 H, s), 4.41 (2 H, q), 5.13 (2 H, s), 6.53 (1 H, m),6.78 (1 H, s), 6.79 (1 H, m), 7.06 (1 H, d), 7.14 (1 H, d), 7.30 (5 H, m),7.50 (2 H, m), 8.03 (1 H, m); MS [MH]+ 400.
Step 3 2-(2-Carboethoxybenzyl)-5-hydroxy-3-methylindole HO
I~
N
COZEt Iodotrimethylsilane (185 ~.1, 1.3 mmol) was added to a stirred solution of 5-benzyloxy-2-(2-carboethoxybenzyl)-3-methylindole (399 mg, 1 mmol) in dichloromethane (3 ml).
After 15 min further iodotrimethylsilane (185 ~1) was added and after 5 min the reaction mixture was diluted 1o with methanol (10 ml). The solvents were evaporated and the residue was dissolved in ether.
The solution was washed with aqueous sodium metabisulphite, aqueous sodium bicarbonate, brine, dried and evaporated to a gum. The crude product was purified by chromatography on Kieselgel 60, eluting with dichloromethane to yield the title compound as a colourless gum (101 mg): NMR 8 (CDCl3) 1.42 (3 H, t), 2.30 (3 H, s), 4.39 (2 H, q), 4.50 (1 H, s), 5.65 (2 H, s),6.52 ( 1 H, m), 6.70 ( 1 H, m), 1 H ( 1 H, s), 6.99 (2 H, m), 7.30 (2 H, m), 8.02 ( 1 H, m); MS [MH]+ 310.
Step 4 1-(2-Carboethoxybenzyl)-3-methyl-5-(4-phenylbenzyloxy)indole / COZEt A mixture of 2-(2-carboethoxybenzyl)-5-hydroxy-3-methylindole (95 mg, 0.31 mmol), 4-phenylbenzyl chloride (68 mg, 0.34 mmol) and potassium carbonate (47 mg, 0.34 mmol) in anhydrous N,N-dimethylformamide (S ml) was stirred at 80°C for 6.5 hr.
The solvent was evaporated and the residue was partitioned between dichloromethane and water.
The organic phase was washed with brine, dried and evaporated to a gum which was chromatographed on Kieselgel 60 eluting with 1:1 v/v dichloromethane/isohexane to yield the title compound as a gum (94 mg): NMR 8 (CDC13 ) 1.43 (3 H, t), 2.32 (3 H, s), 4.40 (2 H, q), 5.18 (2 H, s), 5.68 (2 H, s), 6.55 ( 1 H, m), 6.90 ( 1 H, s), 6.92 ( 1 H, dd), 7.07 ( 1 H, d), 7.28 (2 H, m), 7.35 ( 1 H, d), 7.47 (2 H, dd), 7.6 (6 H, m), 8.04(1 H, m); MS [MH]+ 476.
Step 5 1-(2-Carboxybenzyl)-3-methyl-5-(4-phenylbenzyloxy)indole (Compound 46?) A mixture of 1-(2-carboethoxybenzyl)-3-methyl-5-(4-phenylbenzyloxy)indole (84 mg, 0.18 mmol) and 1M aqueous lithium hydroxide (360 p,1, 0.36.mmo1) in ethanol was stirred for 16 hr.
The reaction mixture was evaporated to dryness and the residue was partitioned between ether and water. The aqueous phase was acidified (2N HCl) to pH 1 and evaporated to dryness. The residue was chromatographed on a Sg C18(EC) IsoluteT"" column (supplied commercially by International Sorbent Technology) eluting with a gradient of 0-40% v/v acetonitrile in water.
Fractions containing the pure title compound by HPLC were pooled and evaporated to yield an amorphous off white solid (30 mg): NMR 8 (d6-DMSO) 2.23 (3 H, s), 5.15 (2 H, s), 5.67 (2 H, s), 6.44 ( 1 H, d), 6.80 (2 H, dd), 7.14 (3 H, m), 7.3 5 (3 H, m), 7.44 ( 1 H, d), 7.47 ( 1 H, d), 7.65 (4 H, m), 7.91 ( 1 H, m); MS [MH]+ 448.
Example 8 Preparation of Compound 47 in Table 1 1-(2-Carboxybenzyl)-3-methyl-5-(2-quinolinylmethyloxy)indole / / ~ CH3 I O \
N I y / N
/ COZH
By the method of Example 1 and using 2-chloromethylquinoline hydrochloride in place of 4-phenylbenzyl chloride, 1-(2-carboxybenzyl)-3-methyl-5-(2-quinolinylmethyloxy)indole was prepared: NMR 8 (db-DMSO) 2.20 (3 H, s), 5.36 (2 H, s), 5.66 (2 H, s), 6.44 (1 H, s), 6.95 (1 H, dd), 7.15 (3 H, m), 7.35 (2 H, m), 7.60 (1 H, dd), 7.70 (1 H, d), 7.78 (1 H, dd), 7.90 (1 H, d), 7.97 ( 1 H, d), 8.02 ( 1 H, d), 8.40 ( 1 H, d).
MS [MH]+ 423.
Example 9 Preparation of Compound 100 in Table 2 1o Step 1 1-(tert-Butoxycarbonyl)-6-hydroxy-1,2,3,4-tetrahydroquinoline HO
J
N
O' _O
A solution of 6-hydroxy-1,2,3,4-tetrahydroquinoline (J. Chem. Soc. Perkin Trans. 1, 1980, 1933-9) (1.0 g, 6.71 mmol) in 1N aqueous sodium hydroxide (8 ml) was stirred during the dropwise addition of a solution of di-tert-butyl dicarbonate (1.74 g, 8 mmol) in tent-butanol (8 ml) over 15 min. Stirnng was continued for 60 hr and the reaction mixture was partitioned between ethyl acetate and water, with acidification of the aqueous phase with 2N hydrochloric 2o acid to pHl. The organic phase was washed with brine, dried and evaporated to a brown oil.
The crude product was chromatographed on Kieselgel 60, eluting with a gradient of 0-10% v/v ethyl acetate in dichloromethane to yield 1-(tert-Butoxycarbonyl)-6-hydroxy-1,2,3,4-tetrahydroquinoline as a pale yellow oil (845 mg): NMR 8 (CDC13) 1.52 (9 H, s), 1.90 (2 H, m), 2.70 (2 H, dd), 3.65 (2H, dd), 5.32 (1 H, s), 6.55 (1 H, d), 6.60 (1 H, dd), 7.44 (1 H, d); MS
[MH]+ 250.
Step 2 1-(tert-Butoxycarbonyl)-6-(2-quinolinylmethyloxy)-1,2,3,4-tetrahydroquinoline / /
\ ~N ~ O \
/
N
O' _O
A mixture of 1-(tert-Butoxycarbonyl)-6-hydroxy-1,2,3,4-tetrahydroquinoline (825 mg, 3.31 mmol), 2-chloromethylquinoline hydrochloride (856 mg, 4.0 mmol) and powdered potassium carbonate (1.10 g, 8.0 mmol) in anhydrous N,N-dimethylformamide (8 ml) was stirred for 16 hr.
The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried and evaporated to dryness. The crude product was chromatographed on Kieselgel 60, eluting with a gradient of 0-10% v/v ethyl acetate in dichloromethane to yield 1-(tert-butoxycarbonyl)-6-(2-quinolinylmethyloxy)-1,2,3,4-tetrahydroquinoline as a pale yellow oil l0 (560 mg): NMR 8 (CDC13) 1.91 (2 H, m), 2.74 (2 H, dd), 3.68 (2 H, dd), 5.37 (2 H, s), 6.75 (1 H, d), 6. 84 ( 1 H, dd), 7. 5 5 (2 H, m), 7. 5 8 ( 1 H, d), 7. 75 ( 1 H, dd), 8.08 ( 1 H, d), 8 .19 ( 1 H, d);
MS [MH]+ 391.
Step 3 6-(2-Quinolinylmethyloxy)-1,2,3,4-tetrahydroquinoline Hydrochloride \
\N O ~ \
/ NJ
H
1-(tert-Butoxycarbonyl)-6-(2-quinolinylmethyloxy)-1,2,3,4-tetrahydroquinoline (550 mg, 1.41.
mmol) was dissolved in ethyl acetate (5 ml) and the solution was treated with 4M hydrogen chloride in ethyl acetate (15 ml). After 60 hr the reaction mixture was evaporated to dryness to yield 6-(2-quinolinylmethyloxy)-1,2,3,4-tetrahydroquinoline hydrochloride as a pale pink solid (478 mg): NMR b (d6-DMSO) 1.98 (2 H, m), 2.80 (2 H, m), 3.30 (2 H, m), 5.50 (2 H, s), 7.04 (2 H, m), 7.24 ( 1 H, d), 7.70 ( 1 H, dd), 7.78 ( 1 H, d), 7.90 ( 1 H, dd), 8.10 ( 1 H, d), 8.16 ( 1 H, d), 8.63 (1 H, d).
Step 4 1-(2-Carboethoxybenzyl)-6-(2-quinolinylmethyloxy)-1,2,3,4-tetrahydroquinoline \
i O
N
N
COZEt A mixture of 6-(2-quinolinylmethyloxy)-1,2,3,4-tetrahydroquinoline hydrochloride (468 mg, 1.43 mmol), ethyl 2-bromomethylbenzoate (696 mg of 76% strength, 2.17 mmol) and 2,6-lutidine (670 ~1, 5.73 mmol) in anhydrous N,N-dimethylformamide (5 ml) was stirred for 2 hr at 95°C. The cooled reaction mixture was partitioned between ethyl acetate and water. The organic 1o phase was washed with brine, dried and evaporated to a dark brown oil. The oil was purified by chromatography on Kieselgel 60, eluting with a gradient of 33-100%v/v dichloromethane in isohexane followed by 0-8% v/v ethyl acetate in dichloromethane to yield 1-(2-carboethoxybenzyl)-6-(2-quinolinylmethyloxy)-1,2,3,4-tetrahydroquinoline as a brown gum (179 mg): NMR 8 (CDCl3) 1.40 (3 H, t), 2.02 (2 H, m), 2.80 (2 H, dd), 3.30 (2 H, dd), 4.36 (2 H, q), 15 4.77 (2 H, s), 5.26 (2 H, s), 6.23 ( 1 H, d), 6.63 ( 1 H, dd), 6.76 ( 1 H, d), 7.28 ( 1 H, m), 7.42 ( 1 H, m), 7.52 ( 1 H, m), 7.70 (2 H, m), 7.80 ( 1 H, d), 8.00 ( 1 H, d), 8.17 ( 1 H, d), 8.3 0 ( 1 H, dd); MS
[MH]+ 453.
Step 5 20 1-(2-Carboxybenzyl)-6-(2-quinolinylmethyloxy)-1,2,3,4-tetrahydroquinoline (Compound 100) A mixture of 1-(2-carboethoxybenzyl)-6-(2-quinolinylmethyloxy)-1,2,3,4-tetrahydroquinoline (179 mg, 0.4 mmol) and 1M aqueous lithium hydroxide (4.0 ml, 4.0 mmol) in ethanol was stirred for 16 hr to give a clear solution. The reaction mixture was evaporated to dryness and the residue 25 was dissolved in warm water (10 ml). The solution was acidified with 2N
hydrochloric acid and then adjusted to pH 2 by the addition of powdered sodium bicarbonate. The pale buff precipitate was filtered off, washed with water and vacuum dried to yield the desired compound (62 mg):
NMR 8 (d6-DMSO) 1.92 (2H, m), 2.75 (2 H, m), 3.30 (2 H, m), 4.68 (2 H, s), 5.18 (2 H, s), 6.12 ( 1 H, d), 6.60 ( 1 H, dd), 6.62 ( 1 H, d), 7.2 8 ( 1 H, d), 7.3 3 ( 1 H, d), 7.45 ( 1 H, dd), 7.5 6 ( 1 H, d), 7.63 (1 H, d), 7.75 (1 H, m), 7.86 (1 H, d), 7.95 (2 H, m), 8.36 (1 H, d); MS
[MH]+ 425.
Example 10 Preparation of Compound 101 in Table 2 Step 1 2,3-dihydro-2-oxo-6-(2-quinolinylmethyloxy)quinoline I\
\ \
N
N- 'O
H
A mixture of 2,3-dihydro-6-hydroxy-2-oxoquinoline (Eur. J. Med. Chem., 1985, 20, 121-5) (2.58 g, 16 mmol), 2-chloromethylquinolin hydrochloride (3.76 g, 17.6 mmol) and powdered potassium carbonate (4.42 g, 32 mmol) in anhydrous N,N-dimethylformamide (24 ml) was stirred at 90°C for 6.5 hr. The cooled reaction mixture was poured into water. The precipitated solid was filtered off, washed with water, air dried and recrystallised from ethanol to yield 2,3-dihydro-2-oxo-6-(2-quinolinylmethyloxy)quinoline (1.71 g): NMR 8 (d6-DMSO) 5.38 (2 H, s), 6.45 ( 1 H, d), 7.28 (2 H, m), 7.33 ( 1 H, d), 7.60 ( 1 H, dd), 7.68 ( 1 H, d), 7.98 ( 1 H, d), 8.02 ( 1 H.
d), 8.40 1 H, d).
2o Step 2 1-(2-Carboethoxybenzyl)-2,3-dihydro-2-oxo-6-(2-quinolinylmethyloxy)quinoline I\
O \ \
N
N- 'O
COzEt 2,3-Dihydro-2-oxo-6-(2-quinolinylmethyloxy)quinoline (800 mg, 2.65 mmol) was added in portions to a stirred suspension of sodium hydride (116 mg of 60% oil dispersion, 2.9 mmol) in anhydrous N,N-dimethyformamide (5 ml). When effervescence ceased a solution of ethyl 2-bromomethylbenzoate ( 1.12 g, 76% strength, 3.5 mmol) in N,N-dimethylformamide (2 ml) was added.
The reaction mixture was stirred for 16 hr and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried and evaporated. Chromatography of the crude product on Kieselgel 60, eluting with a gradient of 0-6% ethanol in dichloromethane, afforded 1-(2-carboethoxybenzyl)-2,3-dihydro-2-oxo-6-(2-quinolinylmethyloxy)quinoline (528 mg) as a brown gum: NMR 8 (CDC13) 5.40 (2 H, s), 5.95 (2 H, s), 6.75 (1 H, d), 6.80 (1 H, d), 7.05 (1 H, d), 7.15 (2 H, m), 7.30 (3 H, m), 7.55 (1 H, dd), 7.64 (1 H, d), 7.68 (1 H, d), 7.75 (1 H, dd), 7.83 (1 H, d), 8.08 (1 H, d), 8.18 (1 H, d); MS [MH]+ 465.
Step 3 1-(2-Carboxybenzyl)-2,3-dihydro-2-oxo-6-(2-quinolinylmethyloxy)quinoline O
...,z. .
A mixture of 1-(2-carboethoxybenzyl)-2,3-dihydro-2-oxo-6-(2-quinolinylmethyloxy)quinoline (500 mg, 1.08 mmol) and 1M aqueous lithium hydroxide (10.8 ml, 10.8 mmol) in ethanol (20 ml) was stirred for 16 hr to give a clear solution. The reaction mixture was evaporated to dryness and the residue was dissolved in water (10 ml). The solution was acidified with 2N hydrochloric 2o acid to pH 1. The resulting precipitate was filtered off, washed with water and vacuum dried to yield 1-(2-carboxybenzyl)-2,3-dihydro-2-oxo-6-(2-quinolinylmethyloxy)quinoline (433 mg):
NMR 8 (d6-DMSO) 5.39 (2 H, s), 5.80 (2 H, s), 6.55 (1 H, d), 6.71 (1 H, d), 7.10 (1 H, d), 7.25 ( 1 H, dd), 7.3 5 (2 H, m), 7.50 ( 1 H, d), 7.60 ( 1 H, dd), 7.68 ( 1 H, d), 7.78 ( 1 H, dd), 8.00 (4 H, m), 8.40 (1 H, d); MS [MH]+ 437.
Example 11 Preparation of Compound 102 in Table 2 ( 1-(2-Carboxybenzyl)-2-oxo-6-(2-quinolinylmethyloxy)-1,2,3,4-tetrahydroquinoline) Using the method of Example 10 and using 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline CChem.
Ber., 1927, 60, 858) in place of 2,3-dihydro-6-hydroxy-2-oxoquinoline, was prepared 1-(2-carboxybenzyl)-2-oxo-6-(2-quinolinylmethyloxy)-1,2,3,4-tetrahydroquinoline:
NMR 8 (d6-DMSO) 2.68 (2 H, dd), 2.96 (2 H, dd), 5.35 (2 H, s), 5.38 (2 H, s), 6.58 (1 H, d), 6.80 (1 H, dd), 6.98 ( 1 H, d), 7.04 ( 1 H, d), 7.33 ( 1 H, dd), 7.43 ( 1 H, dd), 7.65 ( 1 H, dd), 7.72 ( 1 H, d), 7.83 ( 1 H, dd), 7.95 (1 H, d), 8.05 (2 H, m), 8.52 (1 H, d); MS [MH]+ 439.
Example 12 Preparation of Compound 24 in Table 1 Step 1 1-(2-Carboethoxybenzyl)-5-nitroindole o ~.
O
COZEt 2o A mixture of 5-nitroindole (3.0 g, 18.5 mmol), ethyl 2-bromomethylbenzoate (5.0g, slight excess ), potassium carbonate (lO.Og, 72mmo1 ),and potassium iodide (1 crystal), in N,N-dimethylformamide (SOmI) were stirred together at room temperature over the weekend. After pouring into water the mixture was extracted with ethyl acetate. The combined extracts were dried (magnesium sulphate) and evaporated to give an oil. This was columned on Merck 7734 silica using a gradient of ethyl acetate and hexane to give 3.758 of the product:NMR d (d6-DMSO) 1.3 (3 H, t), 4.32 (2 H, q),5.86 (1 H, s), 6.5 (1 H, d), 6.82 ( 1 H, d), 7.35-7.5 (2 H, m), 7.55 (1 H, d), 7.65 (1 H, d), 7.95 (2 H, m) 8.6 (1H, d); MS (MH)+ 325.
Step 2 1-(2-Carbethoxybenzyl)-5-aminoindole H2N \
N
C02Et 1-(2-Carboethoxybenzyl)-5-nitroindole (500 mg, 15.4mmol ), was stirred with 10% Pd/C (50mg ), in methylene chloride (20m1), at room temperature under hydrogen at one atmosphere. After the hydrogen uptake had ceased, the mixture was filtered through celite and evaporated to give the crude product as an oil (450 mg ). This was used without further purification : NMR d ( d6-DMSO ) 1.32 (3 H,t ), 4.38 (2 H ,q ), 4.5 (1H, s (broad) ), 5.64 (2 H , s), 6.21 (1 H, d ), 6.48 (2 H, d ), 6.74 ( 1 H, s ), 6.95 ( 1 H, s ), 7.22 ( 1 H, s ), 7.4 ( 2 H, m ),7.93 ( 1 H, d ); MS (MH)+ 295 .
Step 3 1-(2-Carboethoxybenzyl)-5-( N (N'-benzyl)thioureido)indole \ N N \
S
N
C02Et Benzylisothiocyanate (0.135m1 lmmol ) in methylene chloride (0.5m1) was added at room temperature to a solution of 1-(2-carbethoxybenzyl)-5-aminoindole in methylene chloride (2m1).The mixture was stirred at room temperature overnight, evaporated to dryness and the residue was chromatographed on Merck 7734 silica using a gradient of ethyl acetate and hexane to give the product as a solid : NMR d (d6- DMSO ) 1.36 (3 H, t), 4.35 (2 H, q ), 4.72 (2 H, d ), 5.79 (2 H, s ), 6.5 (2 H, m ), 6.97 (1 H, d ), 7.19-7.54 (10 H, m ), 7.82-7.98 (2 H, m), 9.5 (1 H, s ); MS (MH)+ 444.
Step 4 (Compound 24) A mixture of 1-(2-carboethoxybenzyl)-5-(N (N'-benzyl ) thioureido)indole (200 mg, 0.45mmol) and lithium hydroxide (200 mg, 4.8mmo1 ) in dioxane (5 ml) and water (2 ml ) were stirred together at room temperature for 7hr. The reaction mixture was evaporated to dryness and the to residue was dissolved in water and acidified with 1.0N hydrochloric acid to give a precipitate.
The solid was filtered off, and washed well with water. After drying under vacuum at room temperature an amorphous solid was obtained (160 mg ): NMR d (d6 -DMSO) 4.72 (2 H,d), 5.8 (2 H,s), 6.48 (1 H,d), 6.52 (lH,s), 6.95 (lH,d), 7.18-7.4 (8 H,m), 7.5 (2 H,m), 7.9 (2 H,m), 9.5 (1 H s), 13.21 ( 1 H,s); MS (MH)+ 416 Example 13 Using a method analogous to that described in Example 12, the following compounds were prepared:
Compound Alkylating MS NMR d (d6- DMSO ) number Agent used (MH)+
in step 3 23 / ~ 400 4.27 ( 2 H, d ), 5.72 (2 H, s ), 6.3 (3 H, m), NCO
6.99 (l H,d),7.1-7.42 (9H,m),7.68(1 H,s),7.9(lH,d),8.3(lH,s),13.2(1 H,b) Example 14 Preparation of Compound 85 in Table 2 4-Biphenylcarbonyl chloride (174mg 0.8mmo1) was added to a solution of 1-(2-carbethoxybenzyl)-5-aminoindole (247mg 0.8mmo1), prepared as described in Example 12 step 2, and triethylamine (0.12m1 0.86mmo1 ) in dichloromethane (4m1) After stirring overnight at room temperature the mixture was evaporated and columned on Merck 7734 silica using a gradient of ethyl acetate and hexane to give the desired product (220mg) : NMR
d (d6- DMSO ) 1.35(3H,t),4.36(2H,q),5.75(2H,s),6.4(lH,d),6.52(1 H,d),7.22-8.11(l6H,m), 10.15 (1 H, s ); MS (MH)+ 475.
Example 15 Using a method analogous to that described in Example 14, the following compounds were prepared:
Compd. Alkylating MS NMR d (d6- DMSO ) number Agent used (MH)+

instead of Biphenyl-carbonyl chloride 22 / \ / \ 433 4.4(2H,s),5.7(2H,s),6.35(2H,m), ci 6.78-7.75 ( 16 H, m ), 7.92 ( 1 H, d ) 25 o c~ 385 3.6(2H,s),5.74(2H,s),6.34(lH,m),6.43 /\

(1 H, d ), 7.12-7.48 ( 10 H, m ), 7.92 (2 H, m ), 10.0 (l H,s),13.15(lH,b) 33 ~ 367 0.9 (6 H,d),1.9(3.86(2H,d),5.76(2H,s ~'o ci ),6.3 5 ( 1 H, d ), 6.42 ( 1 H, d ), 7.02-7.42 (5 H, m),7.7(lH,s),7.92(lH,m),9.32(lH,s), 13.18 (lH,s) 51 s 420 4.3 (2 H, s ), 5.76 (2 H, s ), , 6.48 (2 H, d ), 6.98 , / \
, o (1Hd),7.2-7.5(lOH,m),7.98(lH,m), 9.45 (lH,s).

34 / \ / \ 475 5.98 (2H,s),6.39(lH,d),6.55(lH,d), 0 7.22-8.2 (l6H,m),10.8(lH,s), 12.9(1 H,b) Example 16 Preparation of Compound 11 in Table 1 1-(2-Carboethoxybenzyl)-5-nitroindole (200mg 0.62mmo1 ), 1.0N sodium hydroxide (1m1), and ethyl alcohol (5m1) were stirred together at 70° C for 2 hours. The mixture was cooled and then evaporated to dryness. The residue was dissolved in water and acidified with 1.0N hydrochloric acid solution to give a precipitate. The product was obtained after filtering off , washing well with water and vacuum drying.(143mg) : NMR d (d6- DMSO ) 5.9 (2 H, s ), 6.45 (1 H, dd ), 6.8 (lH,d),7.39(2H,m),7.55(lH,d),7.68(lH,d),7.95(2H,m),8.6(lH,s)13.2(1H, s(broad)) ); MS (MH)+297.
to Example 17 Preparation of Compound 52 in Table 1 Step 1 1-(2-Carboethoxybenzyl)-5-cyanoindole.
NC
N
C02Et Sodium hydride (62 mg of60% suspension in oil , 1.55mmo1 ) was added to a solution of 5-cyanoindole (200 mg, 1.4mmol ) in N,N dimethylformamide. After evolution of the hydrogen 2o had ceased , ethyl 2-bromomethylbenzoate (408 mg, l.7mmo1 ) was added and the mixture was stirred at room temperature overnight. After pouring into water and extracting with ethyl acetate, the combined extracts were dried over magnesium sulphate, filtered, and the filtrate was evaporated to leave an oil. The oil was chromatographed on Merck 7734 silica using a gradient of ethyl acetate and hexane to give the product as an oil (290 mg ) : NMR d (d6- DMSO ) 1.32 (3 H,t),4.32(2H,q),5.85(2H,s),6.46(lH,d),6.7(lH,d),7.38-7.98 (6H,m),8.13(lH,s) MS (MH)+ 305.
Step 2 5-Methylamino-1-(2-carbomethoxybenzyl)indole.
H2N I \
/ , N

1-(2-Carboethoxybenzyl)-5-cyanoindole (300 mg, 0.98 mmol ) was dissolved in methyl alcohol (lOml) saturated with ammonia. This solution was hydrogenated at 50° C
and SO atmospheres pressure overnight. After filtering through celite and evaporating an oil was isolated (230mg) to .This was used crude without any further purification: NMR d (CDC13 and D20) 3.93 ( 3 H, s ), 4.15(2H,s)5.77(2H,s),6.42(lH,m)6.58(lH,d)7.1-7.4 (SH,m),7.65(lH,s)8.1(1 H, m ). MS (MH-NH3)+ 278 Step 3 ~5 S-(Methylamino(N-biphenyl))-1-(2-carbomethoxybenzyl)indole.
O
I \ N I \
H
\ / / N
I/

4-Phenylbenzoyl chloride ( 152mg 0.7mmol ) in methlene chloride was added to a mixture of 5-2o methylamino-1-(2-carbomethoxybenzyl)indole (200mg 0.68mmo1 ) and triethylamine (O.lml 0.72mmo1 ) in methylene chloride at room temperature. After stirring overnight at room temperature the mixture was evaporated to dryness and the residue was chromatographed on Merck 7734 silica using a gradient of ethyl acetate and hexane to give the product (150mg):
NMR d (d6- DMSO ) 3.9 (3 H, s ), 4.5 (2 H, d ), 5.76 (2 H, s ), 6.35 (1 H, d ), 6.5 (1 H, d ), 7.04 8.06 ( 16 H, m ), 9.05 ( 1 H, t ); MS (MH)+ 475 Step 4 (Compound 52) A mixture of 5-(methylamino(N-biphenyl))-1-(2-carbomethoxybenzyl)indole (140 mg 0.295 mmol) and lithium hydroxide ( 24.8 mg 0.59mmo1) in dioxane (5m1) and water (2m1) were stirred together at room temperature overnight. The reaction mixture was evaporated to dryness and the residue was dissolved in water and acidified with 1.0N hydrochloric acid to give a precipitate. The solid was filtered off, and washed well with water. After drying under vacuum at 1o room temperature an amorphous solid was obtained (102 mg) : NMR d (d6- DMSO
) 4.55 (2 H, d ), 5.79 (2 H, s ), 6.3 5 ( 1 H, d ), 6.5 ( 1 H, d ), 7.04-8.06 ( 16 H, m ), 9.05 ( 1 H, t ); MS (MH)+ 461 Example 18 Using a method analogous to that described in Example 17, the following compounds were prepared.
Compound Alkylating MS NMR d (d6- DMSO ) number Agent used (MH)+
in step 3 53 , 0 435 4.15 (2H,d),4.24(2H,s),5.79(2H,s w S\~~~ ), 6.3 5 ( 1 H, m ), 6.5 ( 1 H, d ), 7. 04 ( 1 H, d ), 7.2-7.5 8 ( 11 H, m ), 7.92 ( 1 H, m ), 13.3 (l H, s) 39 ~ 381 0.95 (6H,d),1.86(lH,m),3.79(2H,d ~o ci ),4.28 (2H,d)5.85(2H,s),6.4(lH,d ),6.55 (lH,d),7.05(lH,d),7.29(1H, d),7.35-7.72 (SH,m)8.0(1 H,m), 13.2 (lH,s) 54 ~ ~~ 399 3.45 (2H,s),4.32(2H,d),5.78(2H,s I I
i o ),6.32 (lH,m),6.45(lH,d),6.98(1H, d ), 7.15-7.48 ( 10 H, m ), 7.95 (1 H, m ), 8.45 (lH,t),13.2(lH,s 55 O 385 4.55 (2 H,d),5.8(2H,s),6.34(lH,m), 6.48 (1 H, d ), 7.05 (1 H, d ),7.28-7.56 (8 H,m),7.95(3H,m),9.0(lH,t),13.2 (lH,b).

Example 19 Preparation of Compound 37 in Table 1 O
NI _N
I~ H
~N

5-Methylamino-1-(2-carbomethoxybenzyl)indole.(200mg 0.68mmol ) and benzylisocyanate 93.1mg 0.7mmo1 ) were stirred together in methylene chloride (3m1) at room temperature overnight. The mixture was evaporated and then columned on Merck 7734 silica using a gradient of ethyl acetate and hexane to give the product (100mg) ): NMR d (d6- DMSO ) 3.9 (3 H, s ), 4.26(4H,dd),5.75(2H,s),6.34(3H,m),6.48(lH,d),6.95(1Hd),7.12-7.49(lOH,m), 7.91 ( 1 H, m) MS (MH)+ 428 Using similar methodology but with a different alkylating agent, the following compounds were prepared.
Compd. Alkylating MS NMR d (d6- DMSO ) number Agent (MH)+

37 , 414 4.26 (4 H,dd),5.78(2H,s),6.32(3H,m), NCO 6.48 (l H,d),7.0(1Hd),7.14-7.5(IOH,m ),7.92 (lH,m),13.2(lH,s).
38 , 430 4.7 (4 H, s(broad)), 5.8 (2 H, s ), 6.32 (1 H, m ), NCS 6.49 ( 1 H d ), 7.02 ( 1 H, d ), 7.12-8.01 ( 13 H, m )13.25 (lH,b).

56 ~ 444 4.65 (2 H, s (broad)), 5.8 (2 H, s ), 6.3 (1 H, d ), ~NCS 6.48 (1 H, d ), 6.85-8.0 (14 H, m ),13.18 (1 H, s Example 20 Preparation of Compound 57 in Table 1 Step 1 t-Butyl ester of indole-S-oxyacetic acid.
O
~O
o N
H
Sodium hydride (1.3g (60% suspension in oil) 32.Smmo1) was added to a solution of S-l0 hydroxyindole (4.0g 30mmol) in N,N-dimethylformamide .After the hydrogen evolution had ceased t-butylbromoacetate (5.4m1 33.4mmo1 )was added and the mixture was stirred at room temperature overnight. The mixture was poured into water extracted with ether and the combined extracts were washed with water and dried over magnesium sulphate. After filtering the filtrate was evaporated to give an oil. Columning on Merck silica 7734 using a gradient of ethyl acetate and hexane gave the product (5.75g): NMR d (d6- DMSO) 1.4 (9 H, s), 4.58 (2 H, s ) 6.3 (1 H, s ) 6.72 ( 1 H, d ), 6.96 ( 1 H, s ), 7.28 (2 H, m ), MS (MH)+ 248.
Step 2 t-Butyl ester of 1-(2-carboethoxybenzyl)-indole-5-oxyacetic acid O
~O
o I y N
/ C02Et Sodium hydride (920mg(60% suspension in oil ) 23mmo1 ) was added to a solution of the t-Butyl ester of indole-5-oxyacetic acid (5.7g 23mmo1 ) in NN dimetylformamide (SOmI
). When the hydrogen evolution had ceased, ethyl 2-bromomethylbenzoate (5.6g 23mmo1 ) was added. The mixture was stirred at room temperature overnight, and then poured into water.
A$er extracting with ether the combined extracts were washed with water and dried over magnesium sulphate.
The mixture was filtered and the filtrate was evaporated to leave an oil.
Chromatography on Merck 7734 silica using a gradient elutant of ethyl acetate and hexane yielded the pure product.(4.Og ) ): NMR d (d6- DMSO) 1.33 (3 H, t ), 1.42 (9 H, s ), 4.34 (2 H, q ), 4.6 (2 H, s ),5.72(2H,s),6.4(2H,m),6.72(lH,d),7.0(lH,s),7.19(lH,d),7.37(3H,m),7.9 (1 H, d ) MS (MH)+ 410.
Step 3 1-(2-carboethoxybenzyl)-indole-5-oxyacetic acid.
H02C~0 I
N

/ CO2Et Trimethylsilyl triflate (0.89m14.9mmo1 ) was added at room temperature to a stirred solution of the t-butyl ester of 1-(2-carboethoxybenzyl)-indole-5-oxyacetic acid (550mg 1.35mmo1 ) and triethylamine (0.75m15.4mmo1) in dry dioxane(5m1) The mixture was heated at 60° C for three hours . After evaporation the residue was partitioned between water and ether . The combined ether extracts were washed with water brine and then dried over magnesium sulphate. The product was obtained as a crude oil after filtering and evaporating the filtrate. Columning on Merck 7734 silica using a gradient of ethyl acetate and hexane yielded the pure product (350mg) NMR d (d6- DMSO) 1.28 (3 H, t ), 4.3 (2 H, q ), 4.55 (2 H, s ), 5.68 (2 H, s ), 6.33 (2 H, m ), 6.65(lH,d),6.96(lH,s),7.13(lH,d),7.32(3H,m),7.83 (lH,d),12.79(lH,b)MS
(MH)+ 354.
Step 4 1-(2-Carboethoxybenyl)-5-((N- benzyl) oxyacetamido)indole.
O
\ N~O \
H
~N
/ C02Et Benzylamine (0.16m1 1.46mmo1 ), 1-(2-carboethoxybenzyl)-indole-5-oxyacetic acid, (338mg 0.96mmo1 ), and O-(7-azabenzotriazol-1-yl)-NNN',N'-tetramethyluroniumhexafluorophosphate [
HATU ] (550mg 1.45mmo1 ) were stirred together at room temperature in NN
dimethylformamide (3m1). Diisopropylethylamine (0.67m13.85mmo1 ) was added and the mixture was stirred at room temperature for 1 hour. After pouring into I.ON
hydrochloric acid, the mixture was extracted with ether. The combined extracts were washed with 1.0N
hydrochloric acid,water and brine. The extract was dried over magnesium sulphate and evaporated to give the crude product. Chromatography on Merck 7734 silica using a gradient of ethyl acetate and hexane gave the pure product (295mg ): NMR d (d6- DMSO) 1.34 (3 H, t ), 4.35(4H,m),4.52(2H,s),5.78(2H,s),6.4(lH,d),6.44(l H,d),6.8(lH,dd),7.08-7.45 ( 10 H, m ), 7. 9 ( 1 H, m ), 8.6 ( 1 H, t ) MS (MH)+ 443 Step 5 Compound 57 A mixture of 1-(2-carboethoxybenyl)-5-((N- benzyl) oxyacetamido)indole (280mg 0.65mmo1) and lithium hydroxide (136mg, 3.24mmo1 ) in dioxane (3m1) and water (1m1) were stirred together at room temperature overnight. The reaction mixture was evaporated to dryness and the residue was dissolved in water and acidified with 1.0N hydrochloric acid to give a precipitate.
The precipitate was filtered off, and washed well with water. After drying under vacuum at room temperature an amorphous solid was obtained (175mg): NMR d (d6- DMSO ) 4.35 (2 H, d ), l0 4.52(2H,s),5.76(2H,s),6.39(lH,d),6.45(lH,d),6.82(l H,dd),7.1-7.48(IOH,m ),7.95 (1 H, m ),8.6 (1 H, t ), 13.18 (1 H, b ) MS (MH)+ 415.
Example 21 Using a method analogous to that described in Example 20, the following compounds were prepared.
General Structure O
R.N~O \
H ~ /
~COZH
Comp. R MS NMR d (d6- DMSO ) No. (MH)+

58 ~ 433 4.3 (2H,d),4.52(2H,s),5.75(2H,s ),6.35 (lH,m),6.43(1 H,d),6.89(1 H, dd ), 7.0-7.48 ( 9 H, m ), 7.91 (1 H, m),8.65(lH,t) 59 ~ 429 2.75 (2 H, t ), 3.35 (2 H, under water peak),4.4(2H,s),5.75(2H,s),6.35 ( 1 H, m ), 6.42 ( 1 H, d ), 6.78 ( 1 H, dd ), 7.07 ( 1 H, d ), 7.12-7.46 (9 H, m ), 7.92 (lH,m),8.1(lH,t),13.15(lH,s) 60 465 4.62 (2 H, s ), 4.88 (2 H, d ), 5.82 (2 H, s),6.45(2H,m),6.85(lH,dd),7.15 (1 H, d ), 7.25 (1 H, d ), 7.32-7.64 (7 H, m),7.88(lH,t),7.98(2H,m),8.18 (lH,m),8.7(lH,t),13.25(lH,s) 61 I ~ 507 4.6 (2H,s),5.08(2H,s),6.75(2H,s I ~ ~ ),6.35 (lH,d),6.42(lH,d),6.8(15 H,m),7.93(lH,m),9.9(lH,s) 62 ~ 401 4.72 (2H,s),5.8(2H,s),6.42(lH,d ), 6.5 (1 H d ), 6.85-7.52 (9 H, m ), 7.72 (2H,d),8.0(lH,m),10.05(1Hs), 13.15 (1 H s ) 63 I w 445 3.7 (3H,s),4.28(2H,d),4.46(2H,s ~o ~ ),5.75 (2H,s),6.35(lH,m),6.41(1 H, d )6.72-7.48 ( l O H, m ), 7.91 ( 1 H, m ),8.52 (lH,t),13.2(lH,s).

Example 22 Preparation of Compound No 10 in Table 1 Step 1 Methyl-1-(2-carboethoxybenzyl)-indole-5-oxyacetate ) Methyl-1-(2-carboethoxybenzyl)-indole-5-oxyacetate ) was made using an analogous route to that used above for the preparation of the t-butyl ester of 1-(2-carboethoxybenzyl)-indole-5-oxyacetic acid. : NMR d (d6- DMSO) 1.19 (3 H, t ), 1.32 (3 H, t ), 4.0 (2 H, q ), 4.33 (2 H, q ), 4.7(2H,s),5.7(2H,s),6.42(2H,m),6.73(lH,dd),7.03(lH,d),7.18(lH,d),7.37 (3 H, m ), 7.9 (1 H, dd ) MS (MH)+ 382.
Step 2 to Compound 10 Ethyl-1-(2-carboethoxybenzyl)-indole-5-oxyacetate (125mg 0.33mmol),1.ON sodium hydroxide (2m1) and ethyl alcohol ( lOml) were heated together at 70° C for 2 hours. The reaction was cooled and the solvent was evaporated off. The residue was dissolved in water and acidified with 1.0 N hydrochloric acid. The precipitate was filtered offwashed well with water and dried under vacuum at room temperature . (80mg) : NMR d (d6- DMSO) 4.6 (2 H, s), 5.75 (2 H, s ), 6.4 (2 H, m),6.7(lH,m),7.03(lH,s),7.17(lH,d),7.33(3H,m),7.9(lH,d);MS(MH)+326.
Example 23 Preparation of Compound 32 in Table 1 2o Step 1 5-acetoxy-indole \ /'O
O
N
To a solution of 5-hydroxy-indole (12.00g, 90.12mmo1) in pyridine (300m1 ) was added acetic anhydride (9.35m1, 99.13mmo1) and dimethylaminopyridine (100mg, cat). The reaction was stirred for three hours at room temperature when pyridine was evaporated to yield a residue which was partitioned between water and ethyl acetate. The aqueous layer was washed a further three timed with ethyl acetate and the organic layers collected, washed with water, dried over 3o magnesium sulfate and evaporated to yield the desired product (15.82g) as an off white solid. 8 (CDC13, 300MHz) 2.30 (3 H, s), 6.49-6.53 (1 H, m), 6.87-6.92 (1 H, m), 7.12-7.16 (1 H, m), 7.33-7.338 (2 H, m), 8.08-8.8.28 (1 H, s), MS [MH]+176.
Step 2 1-(2-Carboethoxybenzyl)-5-acetoxy-indole Sodium hydride (3,98g of a 60% dispersion on oil, 90.4mmo1) was added to a stirring solution of 5-acetyl-indole (15.82g, 90.40mmo1) in N, N-dimethylformamide (300m1) and 2-Carboethoxybenzylbromide (18.90m1, 108.48mmo1) was added. The reaction was stirred at room temperature for 16 hours and subsequently partitioned between water and ethyl acetate. The 1 o aqueous layer was washed a further three timed with ethyl acetate and the organic layers collected, washed twice with water, dried over magnesium sulfate and evaporated to yield the desired product (30g) 8 (CDC13, 300MHz) 1.37-1.42 (3 H, t), 1.63 (3 H,. s), 4.35-4.42 (2 H, q ), 5.54 (2 H, s), 6.56-6.57 (1 H, d), 7.04-7.13 (2 H, m), 7.37-7.41 (2 H, m), 7.52-7.58 (1 H, t), 7.78-7.81 (1 H, d), 8.02-8.06 (1 H, d), 8.32-8.36 (1 H, d): MS [MH]+338.
Step 3 1-(2-Carboethoxybenzyl)-5-hydroxy-indole HO
N
O
O
A mixture of 1-(2-Carboethoxybenzyl)-5-acetoxy-indole (26.67mg, 79.14mmo1) and sodium ethoxide (9.23mg 21% solution on ethanol, 135.60mmo1) was dissolved in ethanol (1250m1) and heated to 60°C for 1.5 hours, The reaction was cooled to room temperature and partitioned between water and ethyl acetate. The aqueous layer was washed a further three times with ethyl acetate and the organic layers collected, dried over magnesium sulfate and evaporated to yield the desired product which was purified by chromatography on Kieselgel 60 (ART
9385, Merck, Darmstadt) eluting with 20% v/v ethyl acetate in isohexane. Thus was obtained the desired product as an off white solid (13.79g): S (d6-DMSO, 300MHz) 2.29 (3 H, s), 6.52-6.54 (1 H, m), 6.88-6.94 (1 H, m), 7.18-7.20 (1 H, m), 7.34-7.38 (2 H, m), 8.10-8.25 (1 H, s); MS [MH]+176.
Step 4 1-(2-Carboethoxybenzyl)-5-(4-trifluoromethylbenzyloxy)-indole A mixture of 1-(2-Carboethoxybenzyl)-5-hydroxy-indole (3.35g, 1.17mmo1), potassium carbonate (0.57g, 4.09mmol) and 4-trifuoromethyl-benzyl-bromide (0.31 g, 1.29mmo1) in dimethylformamide (3m1) was heated to 100°C for 48 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was further extracted three times ~o with ethyl acetate and the collected organic layers dried over magnesium sulfate and evaporated.
Step 4a In an alternative experiment, step 1 was repeated as described above, except 1.5 molar equivalents of sodium hydride (60% dispersion in oil) were used instead of potassium carbonate, and the reaction stirred at room temperature for 16 hours, not 100°C
for 48 hours.
Step S
1-(2-Carboxybenzyl)-5-(4-trifluoromethylbenzyloxy)-indole (Compound 32) 1-(2-Carboethoxybenzyl)-5-(4-trifluoromethylbenzyloxy)-indole ( from step 1) was dissolved in 1,4-dioxane (5m1) at 60°C, 2M aqueous sodium hydroxide (5m1, lOmmol) was added and the mixture stirred for 16 hours. The 1,4-dioxane was removed and the aqueous residue acidified with 1M hydrochloric acid. The resultant solid precipitate was filtered off washed with toluene and dried to an amorphous off white solid (l2.Smg) 1-(2-Carboxybenzyl)-5-(4-trifluoromethylbenzyloxy)-indole:
8 (db-DMSO, 300MHz) 5.42 (2 H, s), 5.49 (2 H, s), 6.41-6.42 (1 H, d), 6.83-6.87 (1 H, d), 7.08 (1 H, s), 7.30-7.34 (3 H, m), 7.41-7.43 (1 H, t), 7.48-7.49 (1 H, d), 7.56-7.59 (1 H, t), 7.66-7.68 (3 H, m), 7.90-7.93 (1 H, d), 13.07 (1 H, s): MS [MH]+ 426.
Example 24 Using a method analogous to that described in Example 23,the following compounds were prepared.
Compd Mass ion NMR data No.

19 [MH]+ 8 (d6-DMSO, 300MHz) 1.13-1.1 S
(6 H, d), 2.79-400 2.84 (1 H, m), 5.31 (2 H, s), 5.42 (2 H, s), 6.36-6.37 (1 H, d), 6.80-6.84 (1 H, q), 7.05-7.06 (1 H, d), 7.09-7.17 (4 H, m), 7.34-7.44 (3 H, m), 7.55-7.60 ( 1 H, t), 7.66-7.69 ( 1 H, d), 7.90-7.93 ( 1 H, d), 13.05 ( 1 H, s).

21 [MH]+ S (d6-DMSO, 300MHz) 3.59 (3 H, s), 3.68 (6 H, 448 s), 5.26 (2 H, s), 5.42 (2 H, s), 6.36-6.37 (1 H, d), 6.58 (2 H, s), 6.82-6.85 (1 H, d), 7.05 (1 H, s), 7.39-7.47 (3 H, m), 7.54-7.60 (1 H, t), 7.67-69 ( 1 H, d), 7.90-7.93 ( 1 H, d), 13.02 ( 1 H, s).

14 [MH]+ S (d6-DMSO, 300MHz) 3.35 (2 H, s), 3.43 (2 H, 392 s), 6.36-6.37 (1 H, d), 6.79-6.83 (1 H, q), 7.07-7.08 (1 H, d), 7.15-7.17 (2 H, d), 7.23-7.40 (4 H, m), 7.43-7.44 ( 1 H, d), 7.48-7.52 ( 1 H, t), 7.64-7.66 (1 H, d), 7.88-7.80 (1 H, d).

18 [MH]+ 8 (d6-DMSO, 300MHz) 5.37 (2 H, s), 5.42 (2 H, 450 s), 6.36-6.37 (1 H, d), 6.81-6.85 (3 H, m), 6.90-6.95 (3 H, t), 7.05-7.15 (2 H, m) 7.27-7.45 (6 H, m), 7.55-7.60 (1 H, t), 7.68-7.70 (1 H, d), 7.90-7.93 (1 H, d), 13.06 (1 H, s).

16 [MH]+ S (d6-DMSO, 300MHz) 5.25(2 H, s), 5.42 (2 H, 402 s), 5.95 (2 H, s), 6.35-6.36 (1 H, d), 6.71-6.84 (3 H, m), 7.04-7.05 ( 1 H, d), 7.12-7.21 ( 1 H, m), 7.36-7.44 (3 H, m), 7.54-7.59 (1 H, t), 7.66-7.69 ( 1 H, d), 7.90-7.92 ( 1 H, d), 13 .12 ( 1 H, s).
20 [MH]+ b (d6-DMSO, 300MHz) 3.16 (3 H, s), 5.42 (2 H, 436 s), 5.51 (2 H, s), 6.42-6.43 (1 H, d), 6.78-6.86 (1 H, m), 7.08-7.09 (1 H, d), 7.20-7.70 (8 H, m), 7.84-7.90 (2 H, m), 13.04 ( 1 H, s).

6 [MH]+ 8 (d6-DMSO, 300MHz) 5.15 (2 H, s), 5.78 (2 H, 434 s), 6.39-6.43 (2 H, m), 6.78-6.84 (1 H, m), 7.17-7.72 (14 H, m), 7.84-7.91 (1 H, m).

3 [MH]+ 8 (d6-DMSO, 300MHz)5.35 (2 H, s), 5.80 (2 H, 409 s), 6.34-6.35 (1 H, d), 6.48-6.53 (1 H, d), 6.83-6.88 ( 1 H, q), 6.97-7.01 ( 1 H, t), 7.05-7.13 ( 1 H, t), 7.16 ( 1 H, s), 7. 31-7.3 6 ( 1 H, d), 7.47-7.48 ( 1 H, d), 7.58-7.67 (2 H, m), 7.70-7.73 (1 H, d), 7.78-7.83 (1 H, t), 7.97-8.08 (2 H, m), 8.38-8.40 (1 H, d).

4 [MH]+ 8 (d6-DMSO, 300MHz) 5.31 (2 H, s), 5.37 (2 H, 408 s), 6.27-6.29 (1 H, d), 6.70-6.75 (1 H, q), 6.90-6.98 (1 H, d), 7.04-7.08 (2 H, m), 7.09-7.13 (1 H, q), 7.16-7.23 (1 H, t), 7.28-7.31 (2 H, m), 7.34-7.40 (1 H, m), 7.42-7.46 (3 H, m), 7.58-7.66 (2 H, m), 7.85-7.89 (1 H, q).

8 [MH]+ 8 (db-DMSO, 300MHz) 5.78 (2 H, s), 6.48-6.53 344 (2 H, m), 6.82-6.84 (1 H, q), 6.90-6.92 (2 H, d), 7.03-7.08 (1 H, t), 7.23-7.24 (1 H, d), 7.33-7.52 (6 H, m), 7.97-7.99 (1 H, d).

64 [MH]+ 8 (d6-DMSO, 300MHz) 2.37 (3 H, s), 5.27 (2H, 529 s), 5.43 (2 H, s), 6.35-6.36 (1 H, d), 6.86-6.89 (1 H, q), 7.05-7.06 (1 H, d), 7.40-7.59 (7 H, m), 7.67-7.69 (1 H, d), 7.86-7.92 (4 H, m).
65 [MH]+ 8 (d6-DMSO, 300MHz) 3.67 (2 H, s), 5.28 (2 H, 439 s), 5.43 (2 H, s), 6.39-6.40 (1 H, d), 6.82-6.84 (1 H, q), 7.08-7.09 (1 H, d), 7.19-7.23 (1 H, t), 7.36-7.46 (4 H, m), 7.53-7.60 (5 H, m), 7.67-7.70 (1 H, d), 7.89-7.93 (1 H, d).

66 [MH]+ 8 (d6-DMSO, 300MHz) 5.45 (2 H, s), 5.63 (2 H, 459 s), 6.40-6.41 (1 H, d), 6.86-6.91 (2 H, m), 7.06-7.07 (1 H, d), 7.30-7.34 (1 H, t), 7.41-7.62 (6 H, m), 7.81-7.84 (3 H, m).

67 [MH]+ 8 (db-DMSO, 300MHz) 5.42 (2 H, s), 5.63 (2 H, 409 s), 6.43-6.44 (1 H, d), 6.81-6.85 (1 H, q), 7.08-7.09 (1 H, d), 7.38-7.47 (2 H, m), 7.54-7.68 (4 H, m),7.74-7.97 (1 H, t), 7.77-8.03 (3 H, m), 8.21 (1 H, s), 8.90 (1 H, s).

68 [MH]+ b (d6-DMSO, 300MHz) 5.42 (2 H, s), 5.60 (2 H, 409 s), 6.41-6.42 (1 H, d) 6.79-6.83 (1 H, m), 7.08-7.09 (1 H, d), 7.38-7.72 (8 H, m), 7.74-7.92 (2 H, m), 8.10-8.12 (1 H, d), 9.30 (1 H, d).

69 [MH]+ b (db-DMSO, 300MHz) 3.67 (3 H, s), 5.28 (2 H, 457 s), 5.43 (2 H, s), 6.40-6.41 ( 1 H, d), 6.81-6.85 ( 1 H, q), 7.09-7.10 (1 H, d), 7.31-7.60 (8 H, m), 7.67-7.69 (1 H, d), 7.90-7.93 (1 H, d).

Example 25 Preparation of Compound No. 5 in Table 1 Step 1 N
~ r0 rSr Or A solution of 1-(p-toluenesulfonyl)-5-carbomethoxy-indole (13.88g, 42.18mmol) in tetrahydrofuran (100m1) was slowly added to a stirring 1M solution of lithium aluminium hydroxide at 0°C under an argon atmosphere. The temperature of the reaction was controlled below 5°C. The reaction was stirred at 0°C for 15 minutes and was subsequently quenched by dropwise addition of a saturated sodium sulfate solution at 0°C. A
white precipitate formed, which was filtered off and washed with tetrahydrofuran. The filtrate was dried over magnesium sulfate and evaporated to yield a yellow oil. This was purified by chromatography on Kieselgel 60 (ART 9385, Merck, Darmstadt) eluting with 25% v/v ethyl acetate in isohexane. There was thus obtained the title compound (9.00g) as a light yellow glassy oil: 8 (CDC13, 300MHz) 2.34 (3 H, s), 4.71-4.72 (2 H, d), 6.62-6.63 (1 H, d), 7.18-7.20 (2 H, d), 7.29-7.31 (1 H, q), 7.55-7.56 (2 H, d), 7.72-7.74 (2 H, d), 7.98-8.00 (1 H, d): MS [MH]-300.
Step 2 1-(p-toluenesulfonyl)-5-methylchloro-indole N
~r0 rSr Or 1-(p-toluenesulfonyl)-5-methylhydroxy-indole (9.00g, 30mmol) was dissolved in N,N-2o dimethylformamide (90m1). Carbontetrachloride (18.50g, 120mmol) and triphenylphosphine (9.04g, 35mmo1) were added and the reaction was left to stir for 60 hours at room temperature.
Subsequently, the reaction was partitioned between ice water and ethyl acetate. The aqueous phase was further extracted three times with ethyl acetate and the collected organic layers were washed twice with water and once with a saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The oily residue was purified by chromatography on Kieselgel 60 (ART 9385, Merck, Darmstadt) eluting with 50% v/v dichloromethane in isohexane. There was thus obtained the title compound (7.02g) as a white powder. 8 (CDC13, 300MHz) 2.32 (3 H, s), 4.68 (2 H, s), 6.62-6.63 (1 H, d), 7.19-7.24 (2 H, m), 7.32-7.34 (1 H, q), 7.58 (1 H, s), 7.60-7.61 (1 H, s), 7.74-7.76 (2 H, d), 7.94-7.96 (1 H, d): MS
[MH]+ 320.
l0 Step 3 1-(p-toluenesulfonyl)-S-methyl-(N-methylamino)-pyridine-indole / I
\N N I \
/ N
~ ~O
~S~
O' 1-(p-toluenesulfonyl)-5-methylchloro-indole (2.50g, 7.82 mmol) was dissolved in dimethylformamide (100m1) and potassiumiodide (1.56g, 9.38mmo1), potassium carbonate (3.88g, 28.14mmol) and N-methylamino-pyridine (l.Olg, 9.38mmol) were added.
The reaction was heated to 60°C for 16 hours. Subsequently, the reaction was filtered and cooled to room temperature. The filtrate was partitioned between water and diethyl ether and the aqueous layer 2o was extracted a further three times with diethyl ether. The collected organic layers were dried over magnesium sulfate and evaporated. The oily residue was purified by chromatography on Kieselgel 60 (ART 9385, Merck, Darmstadt) eluting with 50% v/v ethyl acetate in isohexane.
There was thus obtained the title compound (580mg)as a clear oil: ~ (CDCl3, 300MHz) 2.34 (3 H, s), 3.07 (3 H, s), 4.88 (2 H, s), 6.49-6.58 (3 H, m), 7.18-7.38 (3 H, m), 7.37 (1 H, s), 7.40-7.46 (1 H, m), 7.53-7.54 (1 H, d), 7.74-7.76 (2 H, d), 7.91-7.93 (1 H, d), 8.15-8.19 (1 H, m): MS
[MH]+ 392.
Step 4 S-methyl-(N-methylamino)-pyridine-indole / I
N I I /
'N
1-(p-toluenesulfonyl)-S-methyl-(N-methylamino)-pyridine-indole (580mg, 1.48mmo1) was dissolved in methanol (40m1) and aqueous 2M sodium hydroxide (5m1, 10.00mmol) was added and heated to 60°C for 48 hours. The reaction was neutralised with 1M
to aqueous hydrochloric acid and the methanol was evaporated. The residue was partitioned between water and ethyl acetate and the aqueous layer was extracted a further three times with ethyl acetate. The collected organic layers were dried over magnesium sulfate and evaporated.
The brown solid obtained was purified by chromatography on Kieselgel 60 (ART
9385, Merck, Darmstadt) eluting with 20% v/v ethyl acetate in isohexane. There was thus obtained the title 15 compound (260mg) as an amorphous white crystalline solid: b (CDC13, 300MHz) 3.09 (3 H, s), 4.87 (2 H, s), 6.46-6.59 (3 H, m), 7.15-7.17 (1 H, d), 7.18-7.20 (1 H, m), 7.29-7.31 (1 H, d), 7.38-7.43 ( 1 H, m), 7.47 (1 H, s), 8.04-8.18 (1 H, s), 8.19-8.20 (1 H, d): MS
[MH]+ 236.
Step 5 20 1-(2-carboethoxybenzyl)-5-(2-(N-methyl-N-(2-pyridyl)-aminomethyl)-indole / ( \N N I \
I / N~
O
O
Sodium hydride (66mg of a 60% dispersion in mineral oil, 1.65mmo1) was added to a stirring solution of S-methyl-(N-methylamino)-pyridine-indole (260mg, l .l Ommol) in N, N-dimethylformamide (5m1). Stirring was continued for three hours. The reaction was then heated to 60°C, ethyl 2-bromomethylbenzoate was added (636mg, 2.42mmo1) and the reaction was allowed to stir at this temperature for 16 hours. Subsequently the reaction was added to water (300m1) and neutralised with sodium bicarbonate then extracted four times with diethyl ether.
The combined organic layers were washed with water, dried over magnesium sulfate and evaporated. The resulting yellow oil was purified by chromatography on Kieselgel 60 (ART
9385, Merck, Darmstadt) eluting with 10% v/v ethyl acetate in isohexane. There was thus obtained the title compound (330mg)as a clear oil: 8 (CDC13, 300MHz) 1.12-1.15 (3 H, t), 3.09 (3 H, s), 4.38-4.43 (2 H, q), 4.86 (2 H, s), 5.77 (2 H, s), 6.49-6.58 (4 H, m), 7.02-7.04 (1H, d), 7.09-7.17 (2 H, m), 7.28-7.36 (2 H, m), 7.38-7.43 (1 H, m), 7.50 (1 H, s), 8.02-8.04 (1 H, m), 8.18-8.21 ( 1 H, m); MS [MH]+ 400.
Step 6 1-(2-carboxybenzyl)-5-(2-(N-methyl-N-(2-pyridyl)-aminomethyl)-indole (Compound 5) \N N
N, O
2o O
1-(2-carboethyoxybenzyl)-5-methyl-(N-methylamino)-pyridine-indole was dissolved in methanol (5m1), 2M aqueous sodium hydroxide (5m1, l Ommol) was added and the mixture stirred for 24 hours at room temperature. The methanol was removed and the aqueous residue acidified with 1M hydrochloric acid. The resultant white solid precipitate was filtered off (lOlmg). A further crop of product was obtained by extracting the aqueous layer with diethyl ether, evaporating solvent and washing the product with isohexane: 8 (db-DMSO, 300MHz) 3.14 (3 H, s), 4.89 (2 H, s), 5.78 (2 H, s), 6.43-6.49 (2 H, m), 6.68-6.72 (1 H, t), 6.92-7.03 (2 H, m), 7.24-7.49 (5 H, m), 7.66-7.75 (1 H, m), 7.91-7.94 (1 H, m), 8.04-8.05 (1 H, d), 13.22 (1 H, s);MS [MH]+ 372.
Example 26 Preparation of Ortho-methoxy Benzyl amide (Compound 13 in Table 1) Step 1 Preparation of diester:
O
O
N
O
O
l0 To a solution of 5-carbomethoxy-indole (3.0 g, 17 mmol) in DMF (50 ml) was added NaH (60%
in oil, 1.02 g, 25.5 mmol). This was stirred for 15 minutes, and ethyl (2-bromo) benzoate (75%, 4.95 g) added. The mixture was stirred for 45 mins, poured into HZO, extracted into ether, washed H20, dried MgS04, filtered, solvent removed. Flash column chromatography (Si02, EtOAc / isohexane) gave the illustrated diester (4.99 g, 87%). NMR d (CDC13, 300MHz) 1.42 (3H, t), 3.92 (3H, s), 4.41 (2H, q), 5.80 (2H, s), 6.47 (1H, dd), 6.68 (1H, d), 7.18-7.34 (4H, m), 7.86 (1H, dd), 8.06 (1H, dd), 8.44 (1H, d); MS [MH]+ 338;
Step 2 Hydrolysis of methyl ester O
HO
N
O
O
To a solution of diester from step 1 (1.0 g, 2.97 mmol) in anhydrous pyridine (5 ml) was added LiI (1.58 g, 11.8 mmol). This was heated to reflux for 20 hours. Solvent was removed and the residue partitioned between 2 M HCl and EtOAc. Water was further extracted with EtOAc. The combined organics were washed with water, brine, dried MgS04, filtered, solvent removed.
Flash column chromatography (Si02, Ethyl Acetate / isohexane) gave 3 (355 mg, 37%) as a to colourless solid. NMR d (CDCl3, 300MHz) 142 (3H, t), 4.41 (2H, q), 5.82 (2H, s), 6.46-6.51 ( 1 H, m), 6.72 ( 1 H, d), 7.20-7.3 6 (4H, m), 7.93 ( 1 H, dd), 8.04-8.10 ( 1 H, m), 8.54 ( 1 H, d); MS
[MH]+324.
Step 3 Compound 13 A mixture of 1-(2-Carboethoxybenzyl)-5-carboxyindole (162 mg, 0.5 mmol) and orthomethoxybenzylamine (200 mg, 1.41 mmol), HATU (285 mg, 0.75 mmol) and diisopropylethylamine (350m1, 2.0 mmol) in dimethylformamide (2.5 ml) was stirred for 22 hours. The reaction mixture was partitioned between diethyl ether and 1M
aqueous hydrochloric 2o acid. The aqueous phase was further extracted twice with diethyl ether. The combined organics were washed with 1M aqueous hydrochloric acid, dried over magnesium sulfate and the solvent removed. The residue was dissolved in ethanol (5 ml) at 60°C, 1M
aqueous lithium hydroxide (1.l ml, 1.1 mmol) was added and the mixture stirred for 2 hours. The ethanol was removed, and the aqueous residue acidified (35% HCl). The resultant solid precipitate was filtered, washed with water and vacuum dried to an amorphous off white solid (168 mg):' NMR d (db-DMSO, 300MHz) 3.83 (3H, s), 4.45 (2H, d), 5.85 (2H, s), 6.40 (1H, d), 6.65 (1H, d), 6.89 (1H, t), 6.98 (1H, d), 7.17-7.25 (2H, m), 7.33-7.44 (3H, m), 7.53 (1H, d), 7.67 (1H, d), 7.99 (1H, dd), 8.24 (1H, s), 8.72 (1H, t); MS [MH]+ 415.
Example 26 Using a method analogous to that described in Example 25, the following compounds were prepared:
O
R1 ~N
R2 ~ /
'N
O
O
Compd MS NMR

No 17 371 (d6-DMSO) 5.85 ("H, s), 6.35-6.44 (1H, m), 6.70 (1H, d), 7.08 (1H, t), 7.28-7.49 (5H, m), 7.57 (1H, d), 7.71 (1H, d), 7.78 (2H, d), 7.93-7.80 (1H, m), 8.28 (1H, s), 10.12 (1H, s), 13.26 ( 1 H, br s);

9 db-DMSO) 3.42-3.64 (8H, m), 5.83 (2H, s), 6.49 (1H, dd), 6.70 (1H, d), 7.15 (1H, dd), 7.31-7.41 (3H, m), 7.52 (1H, d), 7.69 (1H, s), 7.96 (1H, dd), 13.14 (1H, br s);

70 403 (db-DMSO) 1.97 (2H, p), 3.23 (2H, ~, 4.03 (2H, t), 5.87 (2H, s), 6.51 (1H, d), 6.56 (1H, d), 6.89 (1H, s), 7.00 (1H, t), 7.11 (1H, t), 7.21 (1H, s), 7.47 (1H, d), 7.59 (1H, dd), 7.68 ( 1 H, dd), 8.12 ( 1 H, s), 8 .3 3 ( 1 H, t);

71 385 (CDC13) 4.69 (2H, d), 5.80 (2H, s), 6.41-6.47 (2H, m), 6.66 ( 1H, d), 7.18-7.40 (8H, m), 7.63 ( 1 H, dd), 8.15-8.18 (2H, m);

72 415 (db-DMSO) 3.71 (3H, s), 4.41 (2H, d), 5.84 (2H, s), 6.36-6.39 (1H, m), 6.64 (1H, d), 6.88 (2H, d), 7.25 (2H, d), 7.35-7.3 8 (3H, m), 7.52 ( 1 H, d), 7.64 ( 1 H, d), 7.94-7.98 ( 1 H, m), 8.20 (1H, s), 8.84 (1H, t), 13.1 (1H, br s);

73 4194 (d6-DMSO) 4.46 (2H, d), 5.84 (2H, s), 6.36-6.39 (1H, m), 21 6.65 (1H, d), 7.32-7.39 (7H, m), 7.53 (1H, d), 7.65 (1H, d), 7.94-7.98 (1H, m), 8.21 (1H, m), 8.95 (1H, t);

74 4194 (d6-DMSO) 4.48 (2H, d), 5.85 (2H, s), 6.38 (1H, d), 6.66 21 ( 1 H, d), 7.28-7.40 (7H, m), 7.54 ( 1 H, d), 7.65 ( 1 H, d), 7.94-7.99 (1H, m), 8.22 (1H, s), 8.87 (1H, t), 13.30 (1H, br s) 75 4194 (db-DMSO) 4.54 (2H, d), 5.85 (2H, s), 6.37-6.41 (1H, m), 21 6.66 ( 1 H, d), 7.25-7.44 (7H, m), 7.54 ( 1 H, d), 7.68 ( 1 H, d), 7.89-7.98 (1H, m), 8.24 (1H, s), 8.93 (1H, t);

76 415 (d6-DMSO) 3.72 (3H, s), 4.45 (2H, d), 5.85 (2H, s), 6.37-6.40 ( 1 H, m), 6.65 ( 1 H, d), 6.79 ( 1 H, dd), 6.88-6.91 (2H, m), 7.23 (1H, t), 7.35-7.40 (3H, m), 7.53 (1H, d), 7.65 (1H, dd), 7.94-7.978 (1H, m), 8.22 (1H, s), 8.88 (1H, t), 13.23 (1H, br s);

77 399 (d6-DMSO) 2.85 (2H, t), 3.42-3.52 (2H, m), 5.84 (2H, s), 6.37-6.41 (1H, m), 6.63 (1H, d), 7.16-7.40 (8H, m), 7.52 ( 1 H, d), 7. S 8 ( 1 H, d), 7.94-7. 97 ( 1 H, m), 8 .13 1 H, s), 8.43 ( 1 H, t);

78 445 (db-DMSO) 3.71 (3H, s), 3.72 (3H, s), 4.41 (2H, d), 5.84 (2H, s), 6.37-6.40 1 H, m), 6.64 ( 1 H, d), 6.89 ( 1 H, d), 6.93 ( 1 H, d), 7.00 ( 1 H, s), 7.32-7.3 9 (2H, m), 7.53 1 H, d), 7.64 (1H, d), 7.94-7.97 (1H, m), 8.20 (1H, s), 8.83 (1H, t), 13.13 (1H, br s);

79 453 (d6-DMSO) 4.56 (2H, d), 5.85 (2H, s), 6.37-6.40 (1H, m), 6.65 (1H, d), 7.33-7.40 (3H, m), 7.53-7.55 (3H, m), 7.65-7.70 (3H, m), 7.95-7.98 (1H, m), 8.23 (1H, s), 9.02 (1H, t), 13.20 (1H, br s);

80 435 (db-DMSO) 4.96 (2H, d), 5.85 (2H, s), 6.36-6.39 (1H, m), 6.64 ( 1 H, d), 7.3 5-7.5 7 (8H, m), 7.69 ( 1 H, d), 7. 84 ( 1 H, dd), 7.97-7.99 (2H, m), 8.19-8.25 (2H, m), 8.95 (1H, t), 13.23 (1H, br s);
82 453 (db-DMSO) 4.56 (2H, d), 5.85 (2H, s), 6.36-6.40 (1H, m), 6.66 (1H, d), 7.34-7.41 (3H, m), 7.53-7.72 (6H, m),. 7.94-7.97 (1H, m), 8.21 (1H, s), 9.01 (1H, t), 13.30 (1H, br s);

83 429 (db-DMSO) 4.22-4.24 (4H, m), 5.87 (2H, s), 6.37-6.42 (1H, m), 6.69 ( 1 H, d), 6. 8 0 ( 1 H, d), .
7.21 ( 1 H, dd), 7.3 3-7.44 (4H, m), 7.54-7.57 (1H, m), 7.68 (1H, d), 7.97 (1H, d), 8.25 (1H, s), 9.96 (1H, s), 13.20 (1H, br s);

84 377 (db-DMSO) 1.03-1.38 (5H, m), 1.55-1.80 (3H, m), 3.77 (1H, br), 5.84 (2H, s), 6.33-6.37 (1H, m), 6.63 (1H, d), 7.32-7.37 (3H, m), 7.51 (1H, d), 7.60 (1H, d), 7.96 (1H, dd), 8.03 (1H, d), 8.03 ( 1 H, d), 8.15 ( 1 H, s), 13.25 ( 1 H, br s);

50 422 (db-DMSO) 5.90 (2H, d), 6.42 (1H, dd), 6.74 (1H, d), 7.37-7.68 (6H, m), 7.80 (1H, d), 7.94-7.98 (3H, m), 8.39 (1H, s), 8.87 (1H, d), 9.18 (1H, d), 10.60 (1H, s), 13.31 (1H, br s);

40 411 (db-DMSO) 2.97 (2H, dd), 3.23 (2H, dd), 4.62-4.78 (1H, m), 5.84 (2H, s), 6.35-6.39 (1H, m), 6.63 (1H, d), 7.13-7.16 (2H, m), 7.21-7.24 (2H, m), 7.34-7.37 (3H, m), 7.52 (1H, d), 7.63 ( 1 H, d), 7.94-7.97 ( 1 H, m), 8.18 ( 1 H, s), 8.50 ( 1 H, d), 13.24 (1H, br s);

41 463 (db-DMSO) 3.18 (3H, s), 4.58 (2H, d), 5.85 (2H, s), 6.36-6.40 (1H, m), 6.66 (1H, d), 7.35-7.40 (3H, m), 7.53-7.59 (3H, m), 7.66 (1H, d), 7.88 (2H, d), 7.94-7.98 (1H, m), 8.23 (1H, s), 9.04 (1H, t), 13.24 (1H, br s);

26 351 (d6-DMSO) 0.90 (3H, t), 1.29-1.36 (2H, m), 1.45-4.54 (2H, m), 3.26 (2H, q), 5.84 (2H, s), 6.36-6.39 (1H, m), 6.63 (1H, d), 7.33-7.35 (3H, m), 7.52 (1H, d), 7.59 (1H, d), 7.94-7.97 ( 1 H, m), 8.14 ( 1 H, s), 8.27 ( 1 H, t), 13 .21 ( 1 H, br s);

27 475 (db-DMSO) 4.54 (4H, br s), 5.82 (2H, s), 6.40-6.45 (1H, m), 6.5 8 ( 1 H, d), 7.16-7.44 ( 14H, m), 7.51 ( 1 H, d), 7.76 ( 1 H, s), 7.93-7.97 (1H, m), 13.15 (1H, br s);

28 429 (db-DMSO) 4.38 (2H, d), 5.84 (2H, s), 5.97 (2H, s), 6.35-6.39 (1H, m), 6.79 (1H, d), 6.85 (1H, d), 6.92 (1H, d), 7.33-7.39 (1H, m), 7.53 (1H, d), 7.94-7.98 (1H, m), 8.20 (1H, s), 8. 84 ( 1 H, t), 13 .21 ( 1 H, br s);

29 391 (d6-DMSO) 4.63 (2H, d), 5.84 (2H, s), 6.36-6.39 (1H, m), 6.58 (1H, d), 6.92-9.97 (1H, m), 7.01 (1H, d), 7.37-7.40 (3H, m), 7.53 (1H, d), 7.67 (1H, d), 7.94-7.97 (1H, m), 8.19 (1H, s), 9.00 ( 1 H, t), 13 .20 ( 1 H, br s);

48 422 (d6-DMSO) 5.89 (2H, s), 6.42 (1H, d), 6.73 (1H, d), 7.36-7.51 (4H, m), 7.59 ( 1 H, d), 7.77 ( 1 H, d), 7.96-8.01 (2H, m), 8.08 (1H, dd), 8.32 (1H, d), 8.36 (1H, s), 8.57 (1H, s), 8.80 (1H, d), 10.47 (1H, s), 13.25 (1H, br s);

Example 27 Preparation of Compound 49 in Table 1 To a solution of ethyl ester from Example 24 step 2 (74 mg, 0.23 mmol) in ethanol (3 ml) at room temperature was added 1M aqueous sodium hydroxide solution (3 ml). After stirnng for 3 hours the solvent was removed, water was added and the solution acidified with c. HCI. The resultant colourless precipitate was filtered off and washed with water to give the desired compound (50 mg, 74%) as an amorphous colourless solid. NMR d (CDC13/d6-DMSO, 300MHz) 5.70 (2H, s), 6.30-6.37 (1H, m), 6.52 (1H, d), 7.05 (1H, d), 7.11 (1H, d), 7.17 (1H, t), 7.73 (1H, 1o d), 7.96 (1H, t), 8.29 (1H, s); MS [M-1]- 294.
Example 28 Preparation of Compound 17 in Table 1 Step 1 O
A mixture of 6-formylindole (2.43 g, 16.7 mmol) and methyl-2-bromomethyl-benzoic acid (5.8 ml) in and KzC03 in 35 ml DMF was stirred at room temperature fo r18 hours.
The mixture was poured into water and extracted three times with ether. The combined organics were dried over MgS04, filtered and the solvent removed. Flash Column Chromatography (EtOAc /
isohexane) 1o gave 1-(2-Carbomethoxybenzyl)-6-formyl-indole (3.98 g, 81%) as a red solid.
NMR d (CDC13, 300MHz) 3.95 (3H, s), 5.87 (2H, s), 6.49 (1H, dd), 6.66 (1H, d), 7.28-7.37 (3H, m), 7.64 (1H, d), 7.73-7.80 (2H, m), 8.04-8.09 (1H, m), 9.97 (1H, s); MS [MH]+ 294.
Step 2 N
i iN
/O
O
2-Quinoline methylene triphenylphosphonyl bromide (440 mg, 1.0 mmol) and 1-(2-Carbomethoxybenzyl)-6-formyl-indole were dissolved in tetrahydrofuran (20 ml) at 0°C. A 1M
solution of potassium tent-butoxide in tent-butanol (1.0 ml, 1.0 mmol) was added dropwise and the mixture stirred at room temperature for 16 hours before pouring into water and extracting into ether. Flash column chromatography (EtOAc/isohexane) gave 1-(2-Carbomethoxybenzyl)-6-(2-quinolylstyryl)-indole (100 mg, 27%) as a yellow solid. NMR d (db-DMSO, 300MHz) 3.92 (3H, s), 5.86 (2H, s), 6.44 (1H, d), 6.60 (1H, d), 7.37-7.99 (13H, m), 8.22 (1H, d), 8.29 (1H, d);
MS [MH]+ 419.
Step 3 Compound 17 To a solution of 1-(2-Carbomethoxybenzyl)-6-(2-quinolylstyryl)-indole (60 mg, 0.15 mmol) in methanol was added 2M aqueous NaOH solution (100 ml, 0.2 mmol). The mixture was heated to 60°C for 18 hours, cooled, and the methanol removed. Water was added, and the mixture 1o acidified with the addition of 2M aqueous HCl and neutralised with saturated aqueous sodium hydrogen carbonate solution. The resulting red solid precipitate was filtered to give compound 2 (8 mg, 14%) as a red solid. NMR d (CDC13 + TFA, 300MHz) 5.92 (2H, s), 6.38 (1H, d), 6.69 (1H, d), 7.33-8.45 (14H, m), 8.97 (1H, d; MS [MH]+ 406.
Example 29 Preparation of Compound 30 in Table 1 Step 1 To a suspension of product Example 28, step 2 (250 mg, 0.56 mmol) in tetrahydrafuran (7 ml) 2o and methanol (5 ml), was added sufficient sodium hydroxide to cause solvation. The solution was placed in a hydrogen atmosphere overnight in the presence of 10% Pd/C (52 mg). The reaction was filtered through celite~ and the solvent was removed under reduced pressure. The residue was dissolved in methanol (5 ml) and acidified to pH 1 with 1N HCl .
The resulting mixture was stirred for 1 hour at room temperature, then 45 minutes at 40°C, filtered off, washed with water and dried under vacuum at 50°C. The product was obtained (192 mg, 75 %) as a yellow solid, melting point 11 S-120°C. MS [MH]+ 407; required for CZ,Hz2NzOZ.HC1Ø75Hz0):
C: 71.04; H: 5.41; N: 6.14. Found C: 71.15; H: 5.27; N: 6.11.
Example 30 Preparation of Compound 2 in Table 1 Step 1 2-Quinoline methylene triphenylphosphonyl bromide (4.17 g, 8.6 mmol) and 5-formyl-indole were dissolved in THF (20 ml) at 0°C. A 1M solution ofpotassium tert-butoxide in THF(8.6 ml, 8.6 mmol) was added dropwise at 0°C and the mixture stirred at room temperature for 16 hours before pouring into 1N HCl (100 ml) and EtOAc (100 ml). This was filtered, washed with water, suspended in MeOH and 6N HCl (1 ml), filtered, washed with water and dried under vacuum at 65°C to yield 5-(2-quinolylstyryl)-indole (1.79 g, 84%) as a red solid, melting point 265-268°C.
Step 2 _ ~ / ~y N
O
'O
A mixture of 5-(2-quinolylstyryl)-indole (500 mg, 1.63 mmol) and sodium hydride (130.4 mg 60% dispersion in oil, 3.26 mmol) in DMF (20 ml) was strirred for 30 minutes.
Ethyl-2-chloromethyl-benzoic acid (357.6 mg, 1.80 mmol) was added and the reaction was stirred at room temperature for 18 hours. The mixture was poured into water and extracted three times with ether. The combined organics were dried over MgS04, filtered and the solvent removed under reduced pressure. Flash Column Chromatography (EtOAc / isohexane) gave 1-(2-Carboethoxybenzyl)-5-(2-quinolylstyryl)-indole (690 mg, 97%) as a pale yellow gum solid.
Step 3 Compound 2 1o To a solution of 1-(2-Carboethoxybenzyl)-5-(2-quinolylstyryl)-indole (680 mg, 1.57 mmol) in methanol (20m1), water (10 ml) and THF (30 ml) was added aqueous LiOH solution (395.8 mg, 9.43 mmol). The mixture was stirred at room temperature for 18 hours, cooled, and the methanol removed. The mixture was acidified by the addition of 2M aqueous HCl and the resulting red solid precipitate was filtered to yield compound 2 (561.2 mg, 81 %) as an orange solid; Required for C2,HzoN202.HC1Ø20Hz0): C: 72.95; H: 4.85; N: 6.30. Found C: 72.99; H:
5.01; N: 6.15.
Example 31 Preparation of Compound 31 in Table 1 Stepl ci A mixture of 4-hydroxyindole (500 mg, 3.76 mmol) anhydrous ground potassium carbonate (1.56 g, 11.28 mmol)and 7-chloro-2-bromomethyl-quinoline (1.15 g, 4.5 mmol) was dissolved in DMF (20 ml) and stirred at 50°C for 5 hours. The reaction was poured onto water and extracted with EtOAc. The organics were dried over magnesium sulfate and dried under reduced pressure.
Chromatography on silica with EtOAc / toluene as eluent afforded a solid which was recrystallised form toluene to yield 7-chloro-2-methyl-quinoline-4-hydroxyindole (733 mg, 63 %) as an off white solid, melting point 173°C.
Step 2 ci N
O
N
O O
A mixture of 7-chloro-2-methyl-quinoline-4-hydroxyindole (200 mg, 0.65 mmol) and sodium hydride (29.0 mg 60% dispersion in oil, 0.71 mmol) in DMF (10 ml) was strirred for 30 minutes.
Ethyl-2-chloromethyl-benzoic acid (141.0 mg, 0.71 mmol) was added and the reaction was stirred at room temperature for 5 hours. The mixture was poured into water and extracted three times with ethyl acetate. The combined organics were washed with water and a saturated solution of sodium chloride, dried over MgS04, filtered and the solvent removed under reduced pressure.
Flash Column Chromatography (EtOAc / isohexane) gave 1-(2-Carboethoxybenzyl)-4-(7-chloro-2-methyl-quinoline)-hydroxyindole as a yellow solid, melting point 127°C, MS [MH]+470.
Step 3 Compound 31 To a solution of 1-(2-Carboethoxybenzyl)-4-(7-chloro-2-methyl-quinoline)-hydroxyindole (from step 2) in methanol (5m1) and THF (5 ml) was added 2M aqueous LiOH solution (2 M). The reaction was stirred at room temperature for 18 hours and added to water (76 ml) containing 6N
HCl ( 6.1 ml), then stirred for 1 S minutes. The resulting yellow solid precipitate was filtered off and washed with water, then in dried under vacuum at 50°C to yield compound 31 (184 mg, 0.41 mmol), melting point 230-233°C; Required for CZ6H,BNzO,.HC1.): C:
65.15; H: 4.21; N: 5.84.
Found C: 65.49; H: 4.37; N: 5.66.
Example 32 Biological Assays (a) Ligand binding assay to The assay was based on a scintillation proximity assay in which the displacement of radiolabelled [3H] BRL 49653 (rosiglitazone) binding from biotinylated human PPARy recombinant protein was measured. The PPARy ligand binding domain (LBD) of human PPARyl was expressed in E-Coli as a poly his and c-myc tagged fizsion protein.
Compounds of the invention were incubated with [3H] BRL 49653, 30nM (O.lmCi), biotinylated human PPARg LBD protein (150 ng) and streptavidin SPA beads, 0.25 mg/well. Compounds were able to displace radiolabel and so have pharmacological potential as PPARg agonists or antagonists.
(B) Cell transactivation assays:
Assays were performed by transient transfection of Hepalclc7 cells in which compounds of the 2o invention were tested for their ability to activate human PPARa, d and g isoforms. Cells were co-transfected with either PPARa, d and g expression vectors (containing the entire ORF
sequence) and a reporter construct carrying a PPRE linked Lac Z construct.
Cells were transfected using Superfect and cultured in T75 flasks overnight, then plated into 96 well plates and left for 5 hours before the addition of test compound. After a further 24 hours PPAR
activation was quantitated indirectly as (3-Galactosidase activity by hydrolysis of chlorophenol red-(3-D-galactopyranoside (CPRG), measured spectrophotometrically at 580 nm.
Compounds of the invention were active in this assay. For example Compound 3 in Table 1 showed a g transactivation of 79% at a concentration of 10~,M.
According to their activity in transactivation assays and by comparison to the selective PPARg agonist, BRL 49653; compounds of the invention were categorised as either having pharmacological properties consistent with: selective PPARg agonists, partial agonists or non-selective PPAR a/g agonists.
Adipocyte differentiation assay:
3T3L1 preadipocytes were grown in DMEM containing 10% NBCS and 1 day post-confluence cells were cultured in differentiation medium (DMEM containing 5% FCS, 1 ~g/ml insulin, 0.25~M dexamethasone and O.SmM IBMX) in the presence or absence of compounds.
BRL
49653 was used as the positive control and the medium replenished after 3 days. On day 7, cells were lysed and glycerophosphate dehydrogenase activity measured spectrophotometrically at 340nm. Under the conditions of the assay BRL 49653 induces a dose related increase in glycerophosphate dehydrogenase activity. Compounds of the invention were found to activate PPARg in the transactivation assay (vide supra) induce glycerophosphate dehydrogenase activity in 3T3L1 cells in a dose -related manner. For example, Compound 3 in Table 1 showed activity at 81 % as compared to the control at a concentration of l OpM.

Claims (12)

CLAIMS:
1. A use of a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof, in the preparation of a medicament for use in the activation of PPAR, X, Y and Z may represent either bonds or atoms or groups of atoms such that X, Y and Z
together with the nitrogen atom complete an optionally substituted five or six-membered aromatic or non-aromatic ring;
where each R1 is selected from C1-3alkyl, halo, haloC1-3alkyl, C1-3alkoxy, optionally substituted hydrocarbyl or optionally substituted heterocyclyl and n is 0, 1 or 2;
R2 is selected from R4, OQR4, C(O)p R4, S(O)q R4, N(QR6)R7, halo, cyano, carboxy, nitro, (O)CN(QR6)R7, OC(O)N(QR6)R7, NR5C(O)pR6, NR5CON(QR6)R7, NR5CSN(QR6)R7, NR5C(O)OR6, N=CR6R7, S(O)q N(QR6)R7 or NR5S(O)q R6, or R2 is carboxy, CH=CHQR4 or NR5C(O)C(O)R6;
where p is 1 or 2, q is 0, 1, 2 or 3;
R4 is selected from optionally substituted hydrocarbyl or optionally substituted -Q-heterocyclyl groups;
R5, R6 and R7 are independently selected from hydrogen, optionally substituted hydrocarbyl or optionally substituted Qheterocyclyl groups or R6 and R7 together with the atom to which they are attached form a ring which may be optionally substituted and which may comprise one or more heteroatoms;
l is 0 or 1;
each Q is independantly selected from a direct bond, C1-3alkylene or C2-3alkenylene;
each R3 is independently selected from C1-3alkyl, halo, haloC1-3alkyl, C1-3alkoxy and m is 0, 1 or 2.
2. Use of a compound as claimed in claim 1 wherein X is a bond or a group CH2 or C(O); Y-Z-is selected from -CHR17-CHR18-C(O)-, -CHR17-CHR18-CHR19-, where R17, R18 and R19 are independently selected from hydrogen or C1-3 alkyl.
3. Use of a compound as claimed in claim 1 or claim 2 wherein R17, R18, and R14 are all hydrogen.
4. Use of a compound as claimed in any claim from 1 to 3 wherein where X-Y-Z
form an indole group as shown below and A, 1, R1, R2, R3, m and n are as defined in claim 1, 2 or 3.
5. Use of a compound as claimed in any claim from 1 to 3 wherein at all occurences Q is a direct bond and R2 is not carboxy, CH=CHQR4 or NR5C(O)C(O)R6.
6. A compound of formula (IA) or a pharmaceutically acceptable salt or ester thereof, where X is a bond or a group CH2 or C(O); and -Y-Z- is selected from -CR17=CR18-, -C(O)-CR17=CR18-, -CR17=CR18C(O)-, -CHR17-CHR18-C(O)-, -CHR17-CHR18-CHR19-, where R17, R18 and R19 are independently selected from hydrogen or C1-3alkyl;
where each R1 is selected from C1-3alkyl, halo, haloC1-3alkyl, C1-3alkoxy, optionally substituted hydrocarbyl or optionally substituted heterocyclyl and n is 0, 1 or 2;

R2 is selected from R4, OQR4, C(O)p R4, S(O)q R4, N(QR6)R7, halo, cyano, carboxy, nitro, (O)CN(QR6)R7, OC(O)N(QR6)R7, NR5C(O)p R6, NR5CON(QR6)R7, NR5CSN(QR6)R7, NR5C(O)OR6, N=CR6R7, S(O)q N(QR6)R7 or NR5S(O)q R6, or R2 is carboxy, CH=CHQR4 or NR5C(O)C(O)R6;
where p is 1 or 2, q is 0, 1, 2 or 3;
R4 is selected from optionally substituted hydrocarbyl or optionally substituted -Q-heterocyclyl groups;
R5, R6 and R7 are independently selected from hydrogen, optionally substituted hydrocarbyl or optionally substituted Qheterocyclyl groups or R6 and R7 together with the atom to which they are attached form a ring which may be optionally substituted and which may comprise one or more heteroatoms;
l is 0 or 1;
each Q is independantly selected from a direct bond, C1-3alkylene or C2-3alkenylene;
each R3 is independently selected from C1-3alkyl, halo, haloC1-3alkyl, C1-3alkoxy and m is 0, 1 or 2; provided that (i) where the group of sub-formula (a) as defined above is a group of sub-formula (h) and R17 and R18 are hydrogen, R2 is other than (2-ethyl-5,7-dimethyl-3H imidazo [4,5-b]pyridin-3-yl)methyl, or methyl substituted with an aromatic heterocyclic ring containing 2 or 3 nitrogen atoms;
(ii) where the group of sub-formula (a) as defined above is a group of sub-formula (g) as defined above and R17 and R18 are hydrogen, R2 is other than a group S(O)q NR6R7 where q is 2, R6 is hydrogen and R7 is 2-chlorophenyl; or (iii) where the group of sub-formula (a) is a group of sub-formula (i) as defined above and R17 and R18 are hydrogen, either R2 is other than halo, cyano, nitro, C1-5alkyl, C2-5alkenyl, C2-5alkynyl, optionally substituted phenyl or a group OR14, NR14R15 or SR14 where R14 and R15 are selected from hydrogen, C1-5alkyl, C2-5alkenyl or C2-5alkynyl or optionally substituted phenyl, or m is other than 0.
7. A compound of formula (1A) as claimed in claim 6 or 7 wherein R17, R18, and R19 are all hydrogen.
8. A compound of Formula (1A) as claimed in claim 6 or claim 7 where X-Y-Z
form an indole group as shown below wherein A, l, R1, R2, R3, m and n are as defined in claim 6;
provided that where the group of sub-formula (a) as defined above is a group of sub-formula (h) and R17 and R18 are hydrogen, R2 is other than (2-ethyl-5,7-dimethyl-3H
imidazo [4,5-b]pyridin-3-yl)methyl, or methyl substituted with an aromatic heterocyclic ring containing 2 or 3 nitrogen atoms.
9. A compound of Formula (1A) as claimed in claim 6, 7 or 8 wherein R5, R6 and R8 are independently selected from hydrogen;
a hydrocarbyl which is alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkenyl or cycloalkynyl groups optionally substituted by a group selected from halo, cyano, nitro, C(O)a R8, OR8, S(O)b R8, NR9R10, C(O)NR9R10, OC(O)NR9R10, -NR8C(O)a R9, -NR8CONR9R10, N=CR9R10, S(O)b NR9R10 and NR8S(O)b R10 where a is 1 or 2 and b is 0, 1, 2 or 3 (where R8, R9 and R10 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkoxy, aralkyl, cycloalkyl, cycloalkenyl or cycloalkynyl, any of which may themselves be optionally substituted by halo, nitro cyano, alkanoyl such as acetyl, oxo, carboxy or salts or esters thereof, alkoxy such as methoxy, ethoxy or propoxy, aryloxy such as phenoxy, thioalkyl such as thiomethyl, thioethyl or thiopropyl, sulphate, haloalkyl, aryl, carbamate, amino, mono- or di-alkyl amino, aryl, heterocyclyl or aralkyl groups);
a Qheterocyclyl, where Q is defined in claim 1, which is a single or fused ring structure which may be aromatic or non-aromatic in nature and which contains from 2 to 20 ring atoms, at least one of which is a heteroatom, optionally substituted with a group selected from those listed above for hydrocarbyl group, as well as alkyl, alkenyl or alkynyl groups which may be optionally substituted with halo, cyano, nitro, C(O)a R11, OR11, S(O)b R11, NR12R13, C(O)NR11R12, OC(O)NR12R13, -NR11C(O)a R12, -NR11CONR12R13, -N=CR12R13, S(O)b NR12R13 or -NR11S(O)b R12 where R11, R12 and R13 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkoxy, aralkyl, cycloalkyl, cycloalkenyl or cycloalkynyl, and a and b are as defined above;

or R6 and R7 together with the atom to which they are attached form a ring which may be optionally substituted and which may comprise one or more heteroatoms.
10. A compound as claimed in any claim from 6 to 8 wherein at all occurences Q
is a direct bond and R2 is not carboxy, CH=CHQR4 or NR5C(O)C(O)R6.
11. A compound of Formula (IA), as defined in any claim from 7 to 9, for use as a medicament.
12. A pharmaceutical composition comprising a compound of formula (IA), as defined in any claim from 7 to 9, in combination with a pharmaceutically acceptable carrier.
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MXPA02001598A (en) 2002-07-02
EP1210343A2 (en) 2002-06-05
CN1379774A (en) 2002-11-13
ZA200200669B (en) 2003-06-25
AU6583400A (en) 2001-03-13
WO2001012187A3 (en) 2001-06-07
NZ517059A (en) 2004-05-28
IL147821A0 (en) 2002-08-14
JP2003507327A (en) 2003-02-25
NO20020765L (en) 2002-04-17
KR20020020817A (en) 2002-03-15

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