ZA200200669B - 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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ZA200200669B
ZA200200669B ZA200200669A ZA200200669A ZA200200669B ZA 200200669 B ZA200200669 B ZA 200200669B ZA 200200669 A ZA200200669 A ZA 200200669A ZA 200200669 A ZA200200669 A ZA 200200669A ZA 200200669 B ZA200200669 B ZA 200200669B
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optionally substituted
group
formula
hydrogen
compound
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ZA200200669A
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Rodney Brian Hargreaves
Paul Robert Owen Whittamore
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Astrazeneca Ab
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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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    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
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    • 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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    • A61K31/40—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
    • 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
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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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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    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • 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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    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • 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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    • C07D401/12—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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    • C07D405/04—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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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 (PPARY), and so arc 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 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 - 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 i 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 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 > 126mg/d]) 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 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
: © WO 0112187 PCT/GB00/03140 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, uricernia 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 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 ig to focus on the importance of dyslipidemia seen in type 2 diabetes. Much has been made of the . 15 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-
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 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-517357 describe the use of certain indole derivatives as angiotensin HI antagonists. 'WO9808818 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< arf, I i
NG
(R3)_ RSs. )n
COOH 1) . 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 R' is selected from C 1-3alkyl, halo, haloC, alkyl, C;.;alkoxy, optionally substituted hydrocarbyl or optionally substituted heterocyclyland nis 0, 1 or 2;
R? is selected from R*, OQR*, C(0),R*, S(0)(R*, N(QR®)R’, halo, cyano, carboxy, nitro, (O)CN(QR%R’, OC(O)N(QR®) R7, NR*C(0),R®, NR’CON(QR®) R”, NR’CSN(QR%) R,
NR’C(O)OR®, N=CR‘R’, S(0){N(QR®)R’ or NR’S(O)4R’, or R? is carboxy, CH=CHQR" or
NR’C(O)C(O)R®; wherepislor2,qis0,1,2or3;
R'is selected from optionally substituted hydrocarbyl or optionally substituted Qheterocyclyl groups;
R°, Rand R’ are independently selected from hydrogen, optionally substituted hydrocarbyl or optionally substituted Qheterocyclyl groups or R® 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; lis 0 or I;
each Q is independantly selected from a direct bond, Ci.;alkylene or Cz.3alkenylene; each R’ is independently selected from C,.jalkyl, halo, haloC,.;alkyl, Ci.;alkoxy and mis 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 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 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 “thioalkvl” 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 lis 1.
Preferably n 1s O or 1. Ideally nis 0.
Preferably m is O or 1. Ideally mis 0.
Preferably R! is selected from C,.jalkyl, halo, haloC;.;alkyl and Ci .;alkoxy.
Suitably in the compounds of formula (I), X is a bond or a group CH; or C(O); and -Y-Z- is selected from -CR'’=CR"®-, -C(0)- CR''=CR'%-
-CR"’=CR"*C(0)-, -CHR""-CHR"*-C(O)-, -CHR""-CHR '®-CHR"’-, where R'7, R'® and R"? are independently selected from hydrogen or C;_; alkyl such as methyl. Thus, in formula (J), the
Group of sub formula (a)
Y
~z
R-(Q) I x (Rm (a) is suitably selected from a group of sub-formula (b), (c), (d), (e), (£), (g), (h) or (i). o 17 17
R17 SN Xn R18 R18
R%(Q -(Q R%-(Q (Q) N (Q) Ay PN (Q) SN (R3),, | R18 Rm | (R3),,
Cc -
CO — © _, @
R18 N R18 R18 .
R-(Q) RQ) RZ (Q)
N N
R3 N R18 : ~ ~
Rm RU (Rp, e ©) R17 U R17 (9)
N N
(Rr, \ (GYM \ (h) (i) where R%, Q, 1, R® and m are as defined in relation to formula M.
RY, R" and R'® are selected from hydrogen and C,.salkyl. Preferably R'’, R'® and R"’ are all hydrogen.
Preferably compounds of formula (I) are indoles of formula (II) arf JL (R) \
COOH
: © WO001/12187 PCT/GB00/03140 ay
Wherein A, R!, R?, R’?, m and n are as defined above.
The carboxyl group of formula (J) is suitably at the ortho position on the phenyl ning.
Thus in the case of the indoles, a particular preferred group of compounds are those of formula (IA) aff, 1)
N
(R3), >"
HOOC
(oA)
Where present, in the compound of formula (I), (I) or (IIA) R' and R? are suitably 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 (II)
R: arf, TY
N
\
HOOC an where A and R’ are as defined above.
Suitable optional substituents on the five or six membered aromatic or non-aromatic ring formed by X, Y and Z are C;_salkyl, halo, haloC,_salkyl, =O, hydroxy, carboxy and C,4alkoxy.
Preferably X, Y and Z are unsubstututed or substituted by C,.salkyl.
Suitable optional substitutents for any hydrocarbyl groups within R',R* R’,R®andR’ include halo, cyano, nitro, C(O).R®, OR?, S(O),R®, NR°R'’, C(O)NR’R'®, OC(O)NR’R",
NR®C(O).R’, NR®*CONR’R'’, N=CR°R"’, S(O);NR’R'® or NR*S(O),R'® where R®, R® and R'’
are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkoxy, aralkyl, cycloalkyl, cycloalkenyl or cycloalkynyl, any of which may themselves be optionally substituted, aisl or2and bis, 1,2 or 3.
Suitable optional substitutents for any heterocyclyl groups within R!, R*, R®, R® 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, nitro, C(O),R}!, OR!!,
S(O}R'', NR"’R", C(O)NR''R'?, OC(O)NR'’R"*, NR"'C(0).R'%, NR''CONR'?R",
N=CR'’R", S(0),NR"R" or NR! 'S(O)R'? where R'', R'? and R"? are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkoxy, aralkyl, cycloalkyl, 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 R*, R® and R'” include haio, 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 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 R®, R® and R*° may further be substituted by alkyl, alkenyl or alkynyl groups suitably having from 1 to 4 carbon atoms.
The group R? is preferably selected from R*, OQR*, C(0),R*, NR®R’, nitro,
C(O)NRR’, OC(O)N(QR*)R’, NR’ C(O),R®, NR*CON(QR)R’, NR*CSN(QR®R’,
NR’C(O)OR® where Q, R*, R®, R® and R’ are as defined above.
Preferably R” is selected from R*, OQR*, NR°R” and C(O)NR®R’ where Q, R*, R®, R® and R are as defined above.
A particularly preferred group R?is OR®. In this case R* is suitably substituted alkyl, in particular substituted methyl, heterocyclyl or carbocyclyl. In particular, R* 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.
A further preferred group R% is a group NR*C(O)OR® where R® is hydrogen and R® is alkyl, in particular C,. alkyl, such as butyl or tert-butyl.
Particular examples of compounds of formula (I) are listed in Tables 1- 3 below.
R24
R
N OOH
R22 N
Table 1
No] RT [RT RT IR 1 H H H
ES
N= : 0) : 2 H EN H H
NZ oo - 3 H H x H
NZ ONG
4 H H H
CC,
HESS
! . - ; i SNOT
Lo
H C H H
@® ol
TTT ac rT : CL ’ ’ o—
H g 3 H H
J
HE
12 H a H H —N__. 13 H ~o o H H oo ly H =
Cc .
H H H
CD
Oo 16 H AJ H H 0) 17 H H R H H
H o or H H
A i ) WO 01/12187 PCT/GB00/03140 21 H o” H H - : No fo) or 23 H H H
H H
Clon 24 H H H
H H
SN
JT
27 H 9 ° H H
EN
28 H 0 H H 2° AR oN i IAN LT i : [ bo
P29 H Q | H H
J .
Co [I~ ! i | ~ 3, i N 31 ES H H on
F
33 H PY H H H
To 34 H 2 4 H H
N*
H TL H H
N * 36 H JY H H
POR »
N .
O, 37 H 1 H H
Cr NS
H H
38 H 0 H H
OY
H H
39 H 1 H H
Yo NS
H iE []
A
H
41 H I H H
POA .
H
’ © WO o0112187 PCT/GB00/03140 43 H 9 H H ~~) + - 44 H 7 o H H 45 H 8 H H
N eas 46 H ) H CH;
Se ,
AN Oo ) 48 H CL o H H
AL
- H 50 H AN 0 H H
CAL
H
51 H H H H
N+ i 52 H i ° | H H
NYY
IS
Co — | Co 53 H ¢ . H H oH 54 H Ho. H H ~~
Or
55 H CL H H
H
No lo} 56 H 9 H H he .
NTN
H
57 H Q H H
Cyr
H
58 H 1 H H
H
F
59 H P= H H
GUN Io :
N ~
H
IOUS : :
Oh
N . 61
H 2, _ H H 62 H CL 1 H H
N ol
H
63 H H H
Jen
JO i 64 H 8 H H
Na l oo
N oO
H py H H 7 i. o-
CO
N
H ~~ 0” - H H of
H RO OG H H
N [o]
I
70 H NN H H H lw/ ~T 0 71 H 0 H H
Pp
H
) 72 H 0 H H . H ~o 73 H I H H
JOR »
H
Cl 74 H g H H
Cl
H
75 H cl 0 | H H : H {
ANT ! ne { 76 H To H H —C N . A. ;
Cc
ZZ
PE
H
78 H Q H H —0 or
H
79 H 2 H H
J H
=
Fy
H 9 H H
H
81 H 9 H H
A a
H
N
N
82 H Q H H
Res R BN
H o A -
H
AN
H . 85 H H H lx
N._- lo}
Y' “TX 4 ya
N”" COOH
’ © woo1n2187 PCT/GB00/03140
Table 2
IE NJ NA
160 CI CH, i CH; CH;
PON
101 COL CH CH C(O)
FON
102 CI CH, CH; C(O)
PON
’ 5 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 CH; or C(O); and -Y-Z- 1s selected from is selected from -CR'’=CR'®-, -C(0)- CR"’=CR"*-,
CRV=CR'®C(0)-, -CHR’-CHR '®-C(O)-, -CHR’-CHR"*-CHR *-, where R'’, R'* and R"* are independently selected from hydrogen or Ci. 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. R* is other than (2-ethyl-5.7-dimethyl-3H imidazo [4.5-b]pyridin-3 -vl)methvi. or methyl substituted with an aromatic heterocyclic ring containing 2 or 3 nitrogen atoms; (ii) where the group of sub-formuia (a) as defined above is a group of sub-formula (g) as defined above and R'” and R'® are hydrogen, R? is other than a group S(O)NR°R’ where gis 2, R” is hydrogen and R is 2-chlorophenyl; or (iii) where the group of sub-formula (a) is a group of sub-formula (1) as defined above and R"’ and R'? are hydrogen, either R? is other than halo, cyano, nitro, Cy.salkyl, Cz.salkenyl,
C,.salkynyl, optionally substituted phenyl or a group OR', NR'R" or SR'* where R' and R" are selected from hydrogen, C,.salkyl, C,.salkenyl or C,.salkynyl or optionally substituted phenyl, or m 1s 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 conventional methods. In particular however, compounds of formula (I) may be prepared by reacting a compound of formula (III) nef i x _N
RY), RS Rh :
COOR?30 (I) with a compound of formula (IV)
RIM. Iv) where X, Y, Z, R’, R', n and m are as defined in relation to formula MD,
R* is an ester protecting group, in particular an alkyl group, one of R’! or R* is a leaving group and the other is hydrogen or a group which reacts with and eliminates said leaving group,
R¥isabondorisa precursor to R?, and
R¥isa group R? as defined in relation to formula (I) or a part thereof, such that where R*-R* forms a group R’; and thereafter if necessary or desired carrying out one or more of the following steps: (1) removing a protecting group RY: (ii) converting a group R? to a different such group.
Suitable leaving groups for R*! or R* include halogen, such as bromine, mesylate or tosylate. Other examples of leaving groups may comprise hydroxy, where for example this forms part of an acid group (e.g. in the case of R*!, where R* comprises a carbonyl group) which
‘ © WO 01/12187 PCT/GB00/03140 may be condensed, for example with amines of formula (IV) to form compounds where R? 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 R*? include functional type derivatives such as secondary amine groups -NR®-, -O-, C(O), S(0),, C(O)NR®, OC(O)NR®, NR’C(O),, NR’CONR®, NR’*CSNR®,
NR’C(0)O, N=CR®, S(0){NR%0r NR’S(0Q), where p, q and R® and R® are as defined above.
Terminal groups such as R* and R” will then comprise the moiety R* above. Examples of such reactions are illustrated hereinafter. Suitable combinations of compounds of formula (III) and (IV) can be summarised are illustrated in Table 3 - Table 3
SS EE. SU
Yo R°-H
J z hal ! x (RY), Or (RY),
COOR30 {
Yo » SD z
N | R*-hal
XN on (RY, LJ” Rh >
COOR%»
Yo R’-hal
REHN i
N where hal is a halogen atom such as (R3), Tr (RY, bromine or chlorine
COOR%®
<4
DY R~"-hal
HR32
A N
X RY) (Rn n | where hal is a halogen atom such as
COOR3? bromine or chlorine
Deprotection to remove the group R*® 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 R” groups involved and could be derived from the literature.
Compounds of formula (II) may be prepared by reacting a compound of formula (V)
Y<
R31-R32 i x N—H . (Rm 4% where X, Y, Z, R’, and m are as defined in relation to formula (D, and R*' and R*? are as defined in relation to formula (I), with a compound of formula (VI)
R3
Ra? i.
COOR¥ (VI) where R' and n are as defined in relation to formula (I), R*® is as defined in relation to formula (IT) and R*® is a leaving group.
Suitable leaving groups for R*® include those listed above for R*' or R”* and in particular is halo such as bromo. The reaction is suitably effected in an organic solvent such as butanone or 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.

Claims (22)

CLAIMS:
1. A use of a compound of formula (I) Y< nf (R®), (Rn COOH 0) 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 R' is selected from C.;alkyl, halo, haloC,.;alkyl, C,.;alkoxy, optionally substituted * hydrocarbyl or optionally substituted heterocyclyl and nis 0, 1 or 2; - R? is selected from R*, OQR?, C(0),R?, S(0);R*, N(QR®) R’, halo, cyano, carboxy, nitro, (O)CN(QR®)R’, OC(O)N(QR®) R’, NR’C(O),R, NR’CON(QR®) R’, NR’*CSN(QR®) R, NR’C(O)OR®, N=CR‘R’, S(0);N(QR®)R or NR’S(O).R’, or R? is carboxy, CH=CHQR" or NR’C(0)C(O)R®; wherepislor2,qis0,1,2 or 3; R*is selected from optionally substituted hydrocarbyl or optionally substituted -Q-heterocyclyl groups; R°,R%and Rare independently selected from hydrogen, optionally substituted hydrocarbyl or opuonally substituted Qheterocyclyl groups or R® 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; lisOorl; each Q is independantly selected from a direct bond, C,;alkylene or C;.;alkenylene; each R% is independently selected from C,.jalkyl, halo, haloC,_salkyl, C 1-3alkoxy and mis 0, 1 or
2. Use of a compound as claimed in claim 1 wherein X is a bond or a group CH; or C(0); Y-Z- is selected from -CHR'’-CHR'3-C(0)-, -CHR'"-CHR'®-CHR °-, where R'/, R'® and R'® are independently selected from hydrogen or C,.; alkyl.
3. Use of a compound as claimed in claim 1 or claim 2 wherein R'/, R'®, and R'* 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 arf TT) R3 \ ( Im (> )n COOH (IA) and A, 1, R', R?, R%, 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 R? is not carboxy, CH=CHQR* or NR*C(O)C(O)R®.
6. A compound of formula (IA) Y z R&-(Q); [ x (R3)_ Ure n COOH (1A) or a pharmaceutically acceptable salt or ester thereof, where X is a bond or a group CH; or C(O); and -Y-Z- is selected from -CR'’=CR'®-, -C(0)- CR'=CR"-, -CR""=CR"®C(0)-, -CHR!"-CHR'%-C(O)-, -CHR""-CHR'®-CHR "’-, where R"", R'3 and R"’ are independently selected from hydrogen or C,_salkyl; where each R' is selected from C;.3alkyl, halo, haloC,_;alkyl, C,_salkoxy, optionally substituted hydrocarbyl or optionally substituted heterocyclyl and n is 0, 1 or 2;
R? is selected from R*, OQR?, C(O),R*, S(O);R*, N(QR®) R’, halo, cyano, carboxy, nitro, (O)CN(QR®)R’, OC(O)N(QR®)R’, NR’C(0),R®, NR*CON(QR®) R”, NR’*CSN(QR®) R’, NR’C(0)OR®, N=CR’R’, S(0),N(QR® R’ or NR*S(O)_R®, or R? is carboxy, CH=CHQR® or NR’C(O)C(O)R; wherepislor2,qis0,1,2or3; R‘is selected from optionally substituted hydrocarbyl or optionally substituted -Q-heterocyclyl groups; R’, R® and R’ are independently selected from hydrogen, optionally substituted hydrocarbyl or optionally substituted Qheterocyclyl groups or R® 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; lisOor 1; each Q 1s independantly selected from a direct bond, C;salkylene or C;.;alkenylene; each R? is independently selected from Cisalkyl, halo, haloC; alkyl, C; alkoxy and mis 0, 1 or 2; provided that (1) where the group of sub-formula (a) as defined above is a group of sub-formula (h) and R'” and R'® are hydrogen, R? 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; (11) where the group of sub-formula (a) as defined above is a group of sub-formula (g) as defined above and R"" and R'® are hydrogen, Ris other than a group S(O);NR’R’ where q is 2, R® is hydrogen and R’ is 2-chiorophenyl; or (iii) where the group of sub-formula (2) is a group of sub-formula (i) as defined above and R’ and R'® are hydrogen, either R? is other than halo, cyano, nitro, C;_salkyl, C;_salkenyl,
Ca.salkynyl, optionally substituted phenyl or a group OR", NR"R'’ or SR'* where R'* and R" are selected from hydrogen, C;.salkyl, C,.salkenyl or Cs.salkynyl or optionally substituted phenyl, or m is other than 0.
7. A compound of formula (1A) as claimed in claim 6 or 7 wherein R'”, R'%, and R'® 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 eer, 1) (R3),, “(or (R") n COOH IA) wherein A, 1, R!, R%, R, 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 R'7 and R'® are hydrogen, R? is other than (2-ethyl-5,7-dimethyl-3H imidazo [4,5-b]pyridin- 3-yDmethyl, 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 R®, R® and R” 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(0),R?, OR®, S(O)R®, NR°R'’, C(O)NR’R'’, OC(O)NR’R'’, -NR®C(0),R’, -NR*CONR’R", N=CR’R'’, S(O),NR°R'” and NR¥S(O),R'® whereais 1 or2andbis0, 1,2 or 3 (where R®, R’ and R'® 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 ning 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).R'', OR", S(O)R'!, NR'?R"*, C(O)NR''R'?, OC(O)NR'’R"?, -NR''C(0),R'?, -NR!'CONR'?R", -N=CR'*R", S(O),NR'?R" or - NR''S(O)R'? where R"', R'? and R" are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkoxy, aralkyl, cycloalkyl, cycloalkenyl or cycloalkynyl, and a and b are as defined above;
-77- PCT/GB00/03140 or R® 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.
10. A compound as claimed in any claim from 6 to 8 wherein at all occurrences Q is a direct bond and R? is not carboxy, CH=CHQR#* or NR3C(O)C(O)RS.
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.
13. A substance or composition for use in a method of treatment in the activation of PPAR, said substance or composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof, as defined in claim 1, and said method comprising administering said substance or composition.
14. A substance or composition for use in a method of treatment as claimed in claim 13 wherein X is a bond or a group CH, or C(0); Y-Z- is selected from -CHR!7-CHR!8-C(0)-, -CHR!7-CHR!8-.CHR!?-. wherein R!7. R!® and R!? are independently selected from hydrogen or C, 5 alkyl.
15. A substance or composition for use in a method of treatment as claimed in claim 13 or claim 14 wherein R!7, R!® and R14 are all hydrogen.
16. A substance or composition for use in a method of treatment as claimed in any claim from 13 to 15 wherein X-Y-Z form an indole group as shown and defined in claim 4.
17. A substance or composition for use in a method of treatment as claimed in any claim from 13 to 15 wherein at all occurrences Q is a direct bond and R? is not carboxy, CH=CHQR* or NR3C(0)C(O)R®. AMENDED SHEET
-78- PCT/GB00/03140
18. Use as claimed in claim 1, substantially as herein described and illustrated.
19. A compound as claimed in claim 6. substantially as herein described and illustrated.
20. A composition as claimed in claim 12, substantially as herein described and illustrated.
21. A substance or composition for use in a method of treatment as claimed in claim 13, substantially as herein described and illustrated.
22. A new use of a compound as defined in claim 1 or of a pharmaceutically acceptable salt or ester thereof, a new compound, a new composition, or a substance or composition for a new use in a method of treatment, substantially as herein described. AMENDED SHEET
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