WO1999031098A1 - Novel pyridine and pyrimidine derivatives - Google Patents

Abstract

A novel class of substituted pyridine and pyrimidine derivatives, methods for their preparation, pharmaceutical compositions comprising them and use thereof in the treatment and/or prevention of disorders in which a reduction of the blood glucose is beneficial. The derivatives are particularly useful for the treatment and/or prevention of non-insulin dependent diabetes mellitus (NIDDM).

Description

NOVEL PYRIDINE AND PYRIMIDINE DERIVATIVES

FIELD OF THE INVENTION

The present invention relates to novel pyridine and pyrimidine derivatives, to the use of these compounds as medicaments, to pharmaceutical compositions comprising the compounds, and to a method of treatment employing these compounds and compositions. More particularly, the present compounds reduce the blood glucose and are accordingly useful for the treatment of ailments and disorders where a re- duction of the blood glucose is beneficial.

BACKGROUND OF THE INVENTION

Non-insulin dependent diabetes mellitus (NIDDM), also known as maturity-onset diabetes or Type II diabetes, is a condition that poses a major threat to the health of the citizens of the western world. NIDDM accounts for over 85% of diabetes incidents world-wide and about 160 million people are suffering from NIDDM. The number of incidents is expected to increase considerably within the next decades especially in the developing countries. NIDDM is associated with a very high frequency of morbid- ity and premature mortality resulting from a number of serious complications, eg cardiovascular disease (Weir, G.C., Leahy, J.L., (1994) Pathogenesis of non-insulin- dependent (Type II) diabetes mellitus. Joslin's Diabetes Mellitus 13th Ed. (Kahn, C.R., Weir, G.C., Eds.), Lea & Febiger, Malvern, PA, pp. 240-264). NIDDM is characterised by both fasting and postprandial hyperglycaemia resulting from abnormali- ties in insulin secretion and insulin action. A key feature which is almost always found in NIDDM is insulin resistance (Weir, G.C. et al. supra). In the insulin resistant state, the peripheral tissues and the liver exhibit a reduced sensitivity to insulin whereby the stimulation of glucose uptake into muscle and fat cells by insulin is blunted and the suppression of hepatic glucose output by insulin is incomplete. The hyperglycaemia in patients suffering from NIDDM can usually be initially treated by diet, but eventually most NIDDM patients have to take oral antidiabetic agents and/or insulin injections to normalise their blood glucose levels. Currently, the most widely used oral antidiabetic agents are the suiphonylureas which act by increasing the secretion of insulin from the pancreas (Lebovitz, H.E., (1994) Oral antidiabetic agents. Joslin's Diabetes Mellitus 13th Ed. (Kahn, C.R., Weir G.C., Eds.), Lea & Fe- biger, Malvern, PA, pp. 508-529) and the biguanides (eg metformin) which acts on the liver and periphery by unknown mechanisms (Bailey, C.J., Path, M.R.C., Turner R.C. (1996) N. Engl. J. Med. 334:574).

These existing therapies are associated with certain drawbacks: secondary failure occurs in about 10 percent of patients treated with suiphonylureas per year, metformin treatment is rather unspecific, has in certain cases been associated with lactic acidosis, and needs to be given over a longer period of time, ie is not suitable for acute administration (Bailey et al., supra).

Thus, there is a significant and rising need for antidiabetic drugs that have novel mechanisms of action, preferentially drugs that counteract the underlying insulin resistance by increasing insulin action in muscle and fat cells without increasing the circulating plasma levels of insulin.

Several compounds containing a pyrrolopyridinedione skeleton have been disclosed. See for example Da Settimo, A. et al., Eur. J. Med. Chem. (1996), 31 , pp. 49-58; Sladowska, H. et al., Farmaco (1995), 50, pp. 761-768; Russell, G.A. et al., J. Am. Chem. Soc. (1993), 115, pp. 10596-10604; EP 422 456; and EP 361 566. These references feature different pyrrolopyridinedione compounds which are stated to be useful as aldose reductase inhibitors, as compounds with an activity on the nervous system, in photolysis of eg butylmercury halides, as herbicides or as compounds with an effect against cataract, respectively. However, the references neither disclose nor suggest that the pyrrolopyridinedione compounds may be effective to reduce the blood glucose. Furthermore, compounds having a pyrimidopyridazinedione structure have been disclosed for use as chemiluminescent compounds, see Tominaga, Y. et al., Heterocy- cies (1996), 43, pp. 1597-1600; EP 491477; and Van Bergen, T.J. et al., J. Am. Chem. Soc. (1972), 94, pp. 8451-8471. None of these references give any mention of a blood glucose reduction.

The structure

is found in the Available Chemicals Directory (ACD) database and is sold by May- bridge (No. RF 01129). However, no use has been disclosed for the said structure.

Furthermore, Johnson, R. S. et al., J. Chem. Soc, C (1970), pp. 796-800 disclose the following structures for use as possible starting materials for synthesis of gel- semine:

WO 97/16432 discloses 1-(2-[2-isoxazol-3-ylbenzofuran-5-yloxy]ethylamino)-3- phenoxy-2(S)-ol which is stated to be useful to lower blood glucose levels when administered orally to mammals with hyperglycaemia or diabetes owing to a claimed selective β₃-adrenoceptor agonistic activity. The activation of β₃-receptors is stated to stimulate lipolysis (the breakdown of adipose tissue triglycerides to glycerol and free fatty acids).

WO 97/10825 discloses a group of compounds comprising a fused heterocycle such as indole which are stated to be selective β₃-adrenergic agonists useful in the treatment of Type II diabetes and obesity. The compounds are stated to exhibit a marked effect on lipolysis and to effectively increase insulin sensitivity. The structure of these compounds is quite different from that of the present compounds.

In the last decade a class of compounds known as thiazolidinediones have emerged as effective orally active antidiabetic agents that enhance the actions of insulin without promoting insulin secretion, see for example Saltiel, A.R. et al., Thiazolidinediones in the Treatment of Insulin Resistance and Type II Diabetes, Diabetes, Vol. 45, December 1996, pp. 1661-1669; EP 801 063; US Nos. 5,089,514; 4,342,771 ; 4,367,234; 4,340,605; and 5,306,726. These compounds reduce insulin resistance by increasing insulin-dependent glucose disposal and reducing the hepatic glucose output. However, the thiazolidinediones only exert their effect upon administration for a longer period and are accordingly not suitable for acute administration.

The precise mechanism of action of the thiazolidinediones is not known. However, they may interact with a family of nuclear receptors called PPARs (peroxisome prolif- erator-activated receptors). PPAR exists in a heterodimer with another nuclear receptor, RXR (retinoic acid X receptor). WO 97/10819 discloses RXR agonists which are stated to mimic or enhance the antidiabetic effects of thiazolidinedione com- pounds. Furthermore, WO 97/31907 discloses substituted 4-hydroxy-phenylalcanoic acid derivatives with agonist activity to PPAR-gamma which are stated to be useful in the treatment and/or prophylaxis of hyperglycaemia, dyslipidemia and especially in the treatment of Type II diabetes.

The present invention provides a class of pyrimidine and pyridine derivatives which are effective in reducing the blood glucose without affecting the circulating insulin concentrations. Except for the above structures disclosed in the Available Chemicals Directory database and Johnson, R. S. et al., J. Chem. Soc, C (1970), pp. 796-800, respectively, the present compounds are novel per se thereby constituting a further aspect of the invention. The present compounds are very advantageous in exerting their effect after a single administration and are accordingly suitable for both acute and chronic therapy.

The precise mechanism of action of the present compounds is not known. Without being bound to any theory it is believed that they reduce the blood glucose primarily by stimulating the glucose uptake into muscle and fat cells.

DEFINITIONS

The term "C^-alkyl" as used herein represent a branched or straight hydrocarbon group having from 1 to 6 carbon atoms. Typical C^-alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, etf-butyl, pen- tyl, isopentyl, hexyl, isohexyl and the like.

The term "C₂.₆-alkenyl" as used herein represents a branched or straight hydrocarbon group having from 2 to 6 carbon atoms and at least one double bond. Examples of such groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, allyl, iso- propenyl, 1 ,3-butadienyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 1-hexenyl, 2- hexenyl and the like.

The term "C₂.₆-alkynyl" as used herein represents a branched or straight hydrocarbon group having from 2 to 6 carbon atoms and at least one triple bond. Examples of such groups include, but are not limited to, 1-propynyl, 2-propynyl, 1-butynyl, 2- butynyl, 3-methyl-1-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl and the like.

The term "C^-alkoxy" as used herein, alone or in combination, refers to the group -O-C^-alkyl where C^-alky! is as defined above. Representative examples are methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, sec-butoxy, tetf-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.

The term "C^-alkanoyl" as used herein, alone or in combination, refers to the group -CO-V where V is hydrogen or C^-alkyl as defined above. Representative examples are formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, hexanoyl and the like.

The term "C^-alkylthio" as used herein, alone or in combination, refers to the group -S-C^-alkyl where C^-alkyl is as defined above. Representative examples are methylthio, ethylthio, isopropylthio, propylthio, butylthio, pentylthio, hexylthio and the like.

The term "C^-alkylamino" as used herein, alone or in combination, refers to the group

is as defined above. Representative examples are methylamino, ethylamino, isopropylamino, propylamino, butylamino, pentylamino, hexylamino and the like.

The term "di-C^-alkylamino" as used herein, alone or in combination, refers to the group -N-(C₁^-alkyl)₂ where C.,.₆-alkyl is as defined above. Representative examples are dimethylamino, methylethylamino, diethylamino, methyl-n-propylamino, methyl- sec-butylamino, ethyl-n-butylamino, methyl-n-pentylamino, methyl-n-hexylamino and the like.

The term "C^-alkanoylamino" as used herein refers to the group -NH-CO-V where V is hydrogen or C^-alkyl as defined above. Representative examples are formylamino, acetylamino, propionylamino, isobutyrylamino, butyrylamino, valerylamino, hexanoylamino and the like.

The term

where C^-alkoxy is as defined above. Representative examples are methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, sec-butoxycarbonyl, te/f-butoxycarbonyl, pentoxycarbonyl, isopentoxycarbonyl, hexoxycarbonyl, isohexoxycarbonyl and the like

The term "C₃.₈-cycloalkyl" as used herein represents a carbocyclic group having from 3 to 8 carbon atoms eg cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

The term "aryl" as used herein is intended to include carbocyclic aromatic ring systems such as phenyl, naphthyl (1-naphthyl or 2-naphthyl), anthracenyl (1- anthracenyl, 2-anthracenyl, 3-anthracenyl), phenanthrenyl, fluorenyl, indenyl and the like. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 1-(1 ,2,3,4-tetrahydronaphthyl) and 2-(1 ,2,3,4- tetrahydronaphthyl).

The term "heteroaryl" as used herein is intended to include heterocyclic aromatic ring systems containing one or more heteroatoms selected from nitrogen, oxygen and sulphur such as furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, thiadiazinyl, indolyl, isoindolyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl, benzothiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl and the like. Heteroaryl is also intended to include the partially or fully hydrogenated derivatives of the heterocyclic systems enumerated above. Non-limiting examples of such partially or fully hydrogenated derivatives are pyrrolinyl, pyrazolinyl, indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepinyl, diazepinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, oxazolinyl, oxazepinyl, aziridinyl and tetrahydrofuranyl.

The term "C_Lg-aralkyloxycarbonyl" as used herein refers to the group -CO-O-C^- alkylaryl where C.,.₆-alkyl and aryl are as defined above. The term "halogen" means fluorine, chlorine, bromine or iodine.

The term "optionally substituted" as used herein means that the groups in question is unsubstituted or substituted with one or more of the substituents specified. When the groups in question are substituted with more than one substituent the substituents may be the same or different.

Certain of the above defined terms may occur more than once in the structural formulae, and upon such occurrence each term shall be defined independently of the other.

DESCRIPTION OF THE INVENTION

The present invention relates to novel pyrimidine and pyridine derivatives of the general formula I

wherein

X represents

NR⁴ wherein R⁴ represents hydrogen or C^-alkyl which is optionally substituted with halogen, hydroxy, amino, mercapto, C^-alkoxy, C^-alkylthio,

C^-alkylamino or di-C.,_₆-alkylaιτιino, or (NR )₂ wherein R⁴ which may be the same or different have the above meanings;

Y represents N or CR⁵ wherein R⁵ is

hydrogen, halogen, C^-alkoxy, C^-alkylthio or C^-alkylamino,

C,.₆-alkyl, C₂.₆-alkenyl or C₂.₆-alkynyl which are optionally substituted with halogen, hydroxy, amino, mercapto, C^-alkoxy, C^-alkylthio, C^-alkylamino or di- C^-alkylamino, or

C₃^-cycloalkyl, aryl or heteroaryl which are optionally substituted with C^-alkyl, halogen, hydroxy, amino, mercapto, C^-alkoxy, C^-alkylthio, C^-alkylamino or di-C^-alkylamino;

R¹ represents

hydrogen, halogen, C^-alkoxy, C.,.₆-alkylthio or C^-alkylamino,

C^-alkyl, C^-alkenyl or C^-alkynyl which are optionally substituted with halogen, hydroxy, amino, mercapto, C^-alkoxy, C^-alkylthio, C^-alkylamino or di- C^-alkylamino, or

C^-cycloalkyl, aryl or heteroaryl which are optionally substituted with C^-alkyl, halogen, hydroxy, amino, mercapto, C^-alkoxy, C^-alkylthio, C^-alkylamino or di-C^-alkylamino;

Z represents O, S, SO or SO₂; and

R² represents C^-alkyl, C₂.₆-alkenyl or C₂^-alkynyl which are optionally substituted with halogen, hydroxy, C^-alkoxy, amino, nitro, carboxy, C^-alkylamino, di-C^- alkylamino, C^-alkanoylamino, C^-alkanoyl, C^-alkoxycarbonyl, C^- aralkyloxycarbonyl, mercapto, C^-alkylthio, C^-cycloalkyl, aryl or heteroaryl, where

- the aryl moiety of the C^-aralkyloxycarbonyl group, the C₃^-cycloalkyl, aryl and heteroaryl groups optionally are substituted with C^-alkyl, halogen, hydroxy, amino, mercapto, C^-alkoxy, C^-alkylthio, C_Lg-alkylamino or di-C^_g- alkylamino, or

C₃^-cycloalkyl, aryl or heteroaryl which are optionally substituted wit C^-alkyl, halogen, hydroxy,

alkylamino,

aralkyloxycarbonyl, mercapto or C^-alkylthio, where - the aryl moiety of the

group optionally is substituted with

C_Lg-alkylthio, C,_. g-alkylamino or

and

- the group optionally is substituted with halogen, hydroxy, amino, mercapto,

C_Lg-alkylamino or

or

Z and R² taken together may represent C^-cycloalkyl, aryl or heteroaryl which are optionally substituted with C^-alkyl, halogen, hydroxy, C^-alkoxy, amino, nitro, carboxy,

alkanoyl, C^-alkoxycarbonyl, C^-aralkyloxycarbonyl, mercapto or C^-alkylthio;

with the proviso that

when X represents NH, Y represents CH, R represents methyl and Z represents S, R² must not be p-chlorophenyl; and when X represents NH or NCH₃, Y represents CH, R¹ represents methyl and Z represents O, R² must not be methyl;

as well as a pharmaceutically acceptable salt thereof or any optical or geometric isomer or tautomeric form thereof including mixtures of these.

A preferred embodiment of the invention are the compounds of the formula I wherein X represents NR⁴ wherein R⁴ is as defined above; Y represents CR⁵ wherein R⁵ is as defined above; R¹ represents C^-alkyl optionally substituted as defined above; Z represents S or O; and R² represents C^-alkyl, C₂_g-alkenyl or C₂_g-alkynyl which are optionally substituted as defined above or C^-cycloalkyl, aryl or heteroaryl which are optionally substituted as defined above.

A further preferred embodiment of the invention are the compounds of the formula I wherein X represents NH; Y represents CH; R¹ represents C^-alkyl, preferably methyl; and R² represents C^-alkyl, C₂_g-alkenyl or C^-alkynyl which are optionally substituted as defined above or phenyl, cyclohexyl, furyl, thienyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl or pyrrolyl which are optionally substituted as defined above.

Still a further preferred embodiment of the invention are the compounds of the formula I wherein R² represents C^-alkyl optionally substituted with halogen, C^- alkoxy or amino; cyclohexyl optionally substituted with halogen, C^-alkoxy, amino or C^-alkyl; or phenyl optionally substituted as defined above.

A further preferred embodiment of the invention are the compounds of the formula I as defined above wherein R² represents C^-alkyl optionally substituted with halogen, C^-alkoxy or amino; cyclohexyl optionally substituted with halogen, C^-alkoxy, amino or

amino or C^-alkyl. The compounds of the present invention may have one or more asymmetric centres and it is intended that any optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof are included in the scope of the invention.

Additionally, a carbon to carbon double bond may be present in the molecule which may bring about geometric isomers. It is intended that any geometric isomers, as separated, pure or partially purified geometric isomers or mixtures thereof are included in the scope of the invention.

Furthermore, the compounds of the present invention may exist in different tautomeric forms. It is intended that any tautomeric forms which the compounds are able to form are included in the scope of the present invention.

The present invention also encompasses pharmaceutically acceptable salts of the present compounds. Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts. Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulphuric, nitric acids and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulphonic, ethanesulphonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulphonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulphonic, p-toluenesulphonic acids and the like and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference. Examples of metal salts include lithium, sodium, potassium, magnesium salts and the like. Examples of ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like.

Also intended as pharmaceutically acceptable acid addition salts are the hydrates which the present compounds are able to form.

The acid addition salts may be obtained as the direct products of compound synthesis. In the alternative, the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.

The compounds of the present invention may form solvates with standard low molecular weight solvents using methods known to the person skilled in the art. Such solvates are also contemplated as being within the scope of the present invention.

The compounds according to the present invention reduce the blood glucose and are accordingly useful for the treatment of disorders and ailments in which such a reduction is beneficial.

Accordingly, in another aspect the invention relates to a compound of the general formula I'

wherein X represents

NR⁴ wherein R⁴ represents hydrogen or

which is optionally substituted with halogen, hydroxy, amino, mercapto,

(NR⁴)₂ wherein R⁴ which may be the same or different have the above meanings;

Y represents N or CR⁵ wherein R⁵ is

hydrogen, halogen,

C₂.₆-alkenyl or C₂.₆-alkynyl which are optionally substituted with halo- gen, hydroxy, amino, mercapto,

or di-

C^-alkylamino, or

C₃.₈-cycloalkyl, aryl or heteroaryl which are optionally substituted with C^-alkyl, halogen, hydroxy, amino, mercapto,

C,_₆-alkylamino or

R¹ represents

hydrogen, halogen,

C,.₆-aikyl, C₂.₆-alkenyl or C₂.₆-alkynyl which are optionally substituted with halogen, hydroxy, amino, mercapto,

or di-

C₃.g-cycloalkyl, aryl or heteroaryl which are optionally substituted with C^-alkyl, halogen, hydroxy, amino, mercapto, C^-alkoxy, C^-alkylthio, C_Lg-alkylamino or di-C^-alkylamino;

Z represents O, S, SO or SO₂; and

R² represents

C^-alkyl, C₂.₆-alkenyl or C₂.₆-alkynyl which are optionally substituted with halo- gen, hydroxy, C^-alkoxy, amino, nitro, carboxy, C_Lg-alkylamino,

aryl or heteroaryl, where

- the aryl moiety of the

aryl and heteroaryl groups optionally are substituted with C^-alkyl, halogen, hydroxy, amino, mercapto,

or

C₃^-cycloalkyl, aryl or heteroaryl which are optionally substituted with C^-alkyl, halogen, hydroxy, C^-alkoxy, amino, nitro, carboxy, C^-alkylamino, di-C^-alkylamino, C^-alkanoylamino, C^-alkanoyl, C^-alkoxycarbonyl, C^g-aralkyloxycarbonyl, mercapto or

where

- the aryl moiety of the C^-aralkyloxycarbonyl group optionally is substituted with

C^-alkylamino or di-C^-alkylamino and

- the C^-alkyl group optionally is substituted with halogen, hydroxy, amino, mercapto,

or

Z and R² taken together may represent C^-cycloalkyl, aryl or heteroaryl which are optionally substituted with C^-alkyl, halogen, hydroxy, C^-alkoxy, amino, nitro, carboxy,

alkanoyl, C^-alkoxycarbonyl, C^-aralkyloxycarbonyl, mercapto or C^-alkylthio;

as well as a pharmaceutically acceptable salt thereof or any optical or geometric isomer or tautomeric form thereof including mixtures of these for use as a medicament.

The invention also relates to pharmaceutical compositions comprising, as an active ingredient, at least one compound of the formula I' as defined above or a pharma- ceutically acceptable salt thereof or any optical or geometric isomer or tautomeric form thereof including mixtures of these together with one or more pharmaceutically acceptable carriers or diluents.

In a further embodiment the invention relates to a compound of the formula I' as de- fined above

wherein

X, Y and R¹ are as defined for formula I';

Z represents O; and

R² represents

C₂.g-alkenyl or C₂.₆-alkynyl which are optionally substituted with halogen, hydroxy,

C^-alkanoylamino, C^-alkanoyl, C^-alkoxycarbonyl, C^-aralkyloxycarbonyl, mercapto,

C₃.₈-cycloalkyl, aryl or heteroaryl, where - the aryl moiety of the C_Lg-aralkyloxycarbonyl group, the C^-cycloalkyl, aryl and heteroaryl groups optionally are substituted with C^-alkyl, halogen, hydroxy, amino, mercapto,

or di- C^-alkylamino, or

C₃.s-cycloalkyl, aryl or heteroaryl which are optionally substituted with C^-alkyl, halogen, hydroxy, C^-alkoxy, amino, nitro, carboxy, C^-alkylamino,

C_Lg-alkanoylamino,

C_Lg-alkoxycarbonyl,

C^-aralkyloxycarbonyl, mercapto or C^-alkylthio, where - the aryl moiety of the

group optionally is substituted with

- the group optionally is substituted with halogen, hydroxy, amino, mercapto,

as well as a pharmaceutically acceptable salt thereof or any optical or geometric isomer or tautomeric form thereof including mixtures of these.

In another embodiment the invention relates to a compound of the formula I' as defined above

wherein

X, Y and R are as defined for formula I';

Z represents S; and

R² represents

C^-alkyl, C₂.₆-alkenyl or C₂.₆-alkynyl which are optionally substituted with halogen, hydroxy,

C₃.₈-cycloalkyl, aryl or heteroaryl, where - the aryl moiety of the C^-aralkyloxycarbonyl group, the C₃.₈-cycloalkyl, aryl and heteroaryl groups optionally are substituted with C^-alkyl, halogen, hydroxy, amino, mercapto,

or di- C_Lg-alkylamino, or

C^-cycloalkyl or heteroaryl which are optionally substituted with C^-alkyl, halogen, hydroxy,

C^-aralkyloxycarbonyl, mercapto or C^-al ylthio, where - the aryl moiety of the C^-aralkyloxycarbonyl group optionally is substituted with

- the group optionally is substituted with halogen, hydroxy, amino, mercapto,

or

aryl which is optionally substituted with C^-alkyl, iodo, bromo, fluoro, meta- chloro, ortho-chloro, di-chloro, tri-chloro, hydroxy, C^-alkoxy, amino, nitro, carboxy, C^-alkylamino, di-C^-alkylamino, C^-alkanoylamino,

C^g-aralkyloxycarbonyl, mercapto or C_Lg-alkylthio, where

- the aryl moiety of the C^-aralkyloxycarbonyl group optionally is substituted with C^-alkyl, halogen, hydroxy, amino, mercapto, C^-alkoxy, C,.g-alkylthio, C^-alkylamino or di-C^-alkylamino and

- the C^-alkyl group optionally is substituted with halogen, hydroxy, amino, mercapto,

as well as a pharmaceutically acceptable salt thereof or any optical or geometric isomer or tautomeric form thereof including mixtures of these.

In yet another embodiment the invention relates to a compound of the formula I' as defined above wherein X represents

NR⁴ wherein R⁴ represents hydrogen or C^-alkyl which is optionally substituted with halogen, hydroxy, amino, mercapto, C^-alkoxy, C^-alkylthio,

(NR⁴)₂ wherein R⁴ which may be the same or different have the above meanings;

Y represents N or CR⁵ wherein R⁵ is

hydrogen, halogen, C^-alkoxy, C-,.₆-alkylthio or C_Lg-alkylamino,

C₂.₆-alkenyl or C₂.₆-alkynyl which are optionally substituted with halogen, hydroxy, amino, mercapto, C^-alkoxy, C_Lg-alkylthio, C^-alkylamino or di- C^-alkylamino, or

halo- gen, hydroxy, amino, mercapto,

alkyiamino;

R¹ represents

hydrogen, halogen,

C^-alkyl, C₂.₆-alkenyl or C₂.₆-alkynyl which are optionally substituted with halogen, hydroxy, amino, mercapto, C^-alkoxy, C^-alkylthio, C^-alkylamino or di- C^-alkylamino, or C₃.₈-cycloalkyl, aryl or heteroaryl which are optionally substituted with C^-alkyl, halogen, hydroxy, amino, mercapto, C^-alkoxy, C^-alkylthio, C^_g-alkylamino or

Z represents SO or SO₂; and

R² represents

C₂.₆-alkenyl or C₂.₆-alkynyl which are optionally substituted with halo- gen, hydroxy, C^-alkoxy, amino, nitro, carboxy, C^-alkylamino,

aryl or heteroaryl, where

- the aryl moiety of the C^-aralkyloxycarbonyl group, the C₃_₈-cycloalkyl, aryl and heteroaryl groups optionally are substituted with C^-alkyl, halogen, hydroxy, amino, mercapto, C_Lg-alkoxy, C^-alkylthio, C^-alkylamino or di- C^-alkylamino, or

C^-cycloalkyl, aryl or heteroaryl which are optionally substituted with C^-alkyl, halogen, hydroxy,

di-C^-alkylamino, C^-alkanoylamino, C^-alkanoyl, C^-alkoxycarbonyl, C^-aralkyloxycarbonyl, mercapto or

where

- the aryl moiety of the C_Lg-aralkyloxycarbonyl group optionally is substituted with

- the

group optionally is substituted with halogen, hydroxy, amino, mercapto,

or

Z and R² taken together may represent C^-cycloalkyl, aryl or heteroaryl which are optionally substituted with

amino, nitro, carboxy, C^-alkylamino, di-C^-alkylamino, C_Lg-alkanoyiamino, C^- alkanoyl, C^-alkoxycarbonyl, C^-aralkyloxycarbonyl, mercapto or C^_g-alkylthio;

as well as a pharmaceutically acceptable salt thereof or any optical or geometric isomer or tautomeric form thereof including mixtures of these.

Furthermore, the invention relates to the use of the compound of the general formula I' as defined above or a pharmaceutically acceptable salt thereof or any optical or geometric isomer or tautomeric form thereof including mixtures of these for the preparation of a medicament for the treatment and/or prevention of disorders where a reduction of the blood glucose is beneficial.

Furthermore, the invention relates to the use of the compound of the general formula I' as defined above or a pharmaceutically acceptable salt thereof or any optical or geometric isomer or tautomeric form thereof including mixtures of these for the preparation of a medicament for the treatment and/or prevention of disorders where a stimulation of the blood glucose uptake into muscle and fat cells is beneficial.

Additionally, the invention relates to the use of the compound of the general formula I' as defined above or a pharmaceutically acceptable salt thereof or any optical or geometric isomer or tautomeric form thereof including mixtures of these for the preparation of a medicament for the treatment and/or prevention of disorders involving elevated plasma blood glucose.

The present invention also relates to a method for the treatment of disorders in which a reduction of the blood glucose is beneficial the method comprising administering to a subject in need thereof an effective amount of a compound of the formula I' as defined above or a pharmaceutically acceptable salt thereof or any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutical composition comprising the same as defined above. Owing to the efficiency of the present compounds to reduce the blood glucose they are useful for the treatment and/or prevention of ailments and disorders involving elevated plasma blood glucose, such as hyperglycaemia. Furthermore, they may find use in the treatment and/or prevention of dyslipidemia, Type I diabetes, NIDDM, hy- pertriglyceridemia, syndrome X, insulin resistance, impaired glucose tolerance (IGT), obesity, diabetes as a consequence of obesity, diabetic dyslipidemia, hyperlipidemia, cardiovascular diseases and hypertension.

In a preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or prevention of IGT.

In a further preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or preven- tion of NIDDM.

In another preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from IGT to NIDDM.

In yet another preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from NIDDM to insulin requiring Type II diabetes.

In a further preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or prevention of Type I diabetes. Such treatment and/or prevention is normally accompanied by insulin therapy.

PHARMACEUTICAL COMPOSITIONS The compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses. The pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adju- vants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy,19^th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.

The pharmaceutical compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intra- dermal) route, the oral route being preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.

Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, they can be prepared with coatings such as enteric coatings or they can be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well-known in the art.

Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.

Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot injectable formulations are also contemplated as being within the scope of the present invention. Other suitable administration forms include suppositories, sprays, ointments, cremes, gels, inhalants, dermal patches, implants etc.

A typical oral dosage is in the range of from about 0.001 to about 100 mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kg body weight per day, and more preferred from about 0.05 to about 10 mg/kg body weight per day administered in one or more dosages such as 1 to 3 dosages. The exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.

The formulations may conveniently be presented in unit dosage form by methods known to those skilled in the art. A typical unit dosage form for oral administration one or more times per day such as 1 to 3 times per day may contain of from 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, and more preferred from about 0.5 mg to about 200 mg.

For parenteral routes, such as intravenous, intrathecal, intramuscular and similar ad- ministration, typically doses are in the order of about half the dose employed for oral administration.

The compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof. One example is an acid addition salt of a compound having the utility of a free base. When a compound of formula I or I' contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of a free base of formula I or I' with a chemical equivalent of a pharmaceutically acceptable acid, for example, inorganic and organic acids. Representative examples are mentioned above. Physiologically acceptable salts of a com- pound with a hydroxy group include the anion of said compound in combination with a suitable cation such as sodium or ammonium ion. For parenteral administration, solutions of the compounds of formula I or I' in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil may be employed. Such aqueous solutions should be suitable buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. The aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.

Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid or lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene or water. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The pharmaceutical compositions formed by combining the novel compounds of formula I and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of admini- stration. The formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.

Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient. These formulations may be in the form of powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion.

If a solid carrier is used for oral administration, the preparation may be tabletted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge. The amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.

A typical tablet which may be prepared by conventional tabletting techniques may contain:

Core:

Active compound (as free compound or salt thereof) 5.0 mg

Lactosum Ph. Eur. 67.8 mg

Cellulose, microcryst. (Avicel) 31.4 mg

Amberlite 1.0 mg

Magnesii stearas Ph. Eur q.s.

Coating:

HPMC approx 9 mg

Mywacett 9-40 T* approx. 0.9 mg

*Acylated monoglyceride used as plasticizer for film coating.

If desired, the pharmaceutical composition of the invention may comprise the compound of the formula I' in combination with further pharmacologically active substances eg an antidiabetic or other pharmacologically active material, including other compounds for the treatment and/or prophylaxis of insulin resistance and diseases wherein insulin resistance is the pathophysiological mechanism. Suitable antidiabet- ics comprise insulin, GLP-1 derivatives such as those disclosed in WO 98/08871 to Novo Nordisk A/S which is incorporated herein by reference as well as orally active hypoglycaemic agents. The orally active hypoglycaemic agents preferably comprise suiphonylureas (eg tolbutamide, glibenclamide, glipizide and glicazide), biguanides (eg metformin), oxadiazolidinediones, thiazolidinediones (eg troglitazone, ciglitazone, pioglitazone, rosiglitazone and the compounds disclosed in WO No 97/41097 to Dr. Reddy's Research Foundation, especially 5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2- quinazolinyimethoxy]phenyl]-methyl]-2,4-thiazolidinedione), glucosidase inhibitors (eg acarbose), glucagon antagonists, GLP-1 agonists, potassium channel openers, insulin sensitizers, hepatic enzyme inhibitors, glucose uptake modulators, compounds modifying the lipid metabolism, compounds lowering food intake, PPAR and RXR agonists and agents acting on the ATP-dependent potassium channel of the β-cells (eg glibenclamide, glipizide, glicazide and repaglinide).

Furthermore, the compounds according to the invention may be administered in combination with antiobesity agents or appetite regulating agents.

Such agents may be selected from the group consisting of CART agonists, NPY antagonists, MC4 agonists, orexin antagonists, H3 antagonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, β3 agonists, MSH agonists, CCK agonists, serotonin re-uptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists, growth hormone, growth hormone releasing compounds, glucagon, TRH agonists, uncoupling protein 2 or 3 modulators, leptin agonists, DA agonists (bromocriptin, doprexin), lipase/amylase inhibitors, PPAR modulators, RXR modulators or TR β agonists.

Specific examples are leptin, amphetamine, dexfenfluramine, sibutramine and oriistat.

The preparation of the compounds according to the present invention can be realised in many ways. The starting materials are either known compounds or compounds which may be prepared in analogy with the preparation of similar known compounds. The preparation of the compounds of this invention is illustrated in the scheme below. The synthesis can generally be achieved using the two methods A and B to give products of the general formula la according to the invention where X, Y and R¹ are as defined for formula I and A¹ = oxygen or sulphur. When A¹ = sulphur a second step may be employed to give compounds of the general formula lb according to the invention where X, Y and R¹ are as defined for formula I and A² = SO or SO₂. Method A involves the substitution of a chlorine atom (LG = Cl) and method B involves substitution of the methylsulphonyl group (LG = SO₂CH₃).

III la lb

HA¹R² III is first deprotonated by a base such as sodium hydride (NaH), the resulting reactive species then displaces the leaving group LG on structure II to form com- pounds of structure la according to the invention. The oxidation step can be carried out for example using potassium peroxymonosulphate to provide compounds of structure lb according to the invention. In some cases, appropriate protection methodology may need to be employed to avoid unwanted oxidations.

In general, the above methods are suitable for preparing the compounds of the formula I according to the present invention except for such compounds of the formula where Z and R² taken together represent C₃.₈-cycloalkyl, aryl or heteroaryl which are optionally substituted as defined for formula I. The preparation of such compounds are illustrated in example 23.

The present invention is further illustrated by the following representative examples, which are, however, not intended to limit the scope of protection in any way. EXAMPLES

In the examples the following terms are intended to have the following general meanings:

DMF: dimethylformamide

DMSO: dimethylsulphoxide

EtOAc: ethyl acetate

EtOH: ethanol

TFA: trifluoroacetic acid

THF: tetrahydrofuran mp: melting point (uncorrected)

The structures of the compounds are confirmed by assignment of NMR spectra (from which representative peaks are quoted) and by mass spectroscopy MS and/or micro- analysis where appropriate. The compounds used as starting materials are either known compounds or compounds which can be prepared by methods known per se. NMR spectra were recorded on Bruker 300 MHz and 400 MHz instruments. Mass Spectra were run on a Finnigan MAT TSQ70B as SP-MS. Flash chromatography was carried out on Merck silica gel 60 (Art 9385). High performance liquid chromatography (HPLC) was carried out on a Merck Hitachi model L6200A Intelligent chromatograph interfaced to a Merck Hitachi L4000A UV detector to a LiChrospher 100 reversed phase C₁₈ column (250 x 4 mm, 5 μm, 100 A; eluant flow rate 1 mL/min). Retention times are given in minutes.

Example 1

6-Methyl-4-phenoxy-1 H-pyrrolo[3.4-c]pyridine-1.3(2H)-dione

i) 4-chloro-6-methylpyrrolo[3,4-c]pyridine-1 ,3-dione

4-hydroxy-6-methylpyrrolo[3,4-c]pyridine-1 ,3-dione was prepared using the published route (Dickinson, CL. J. Amer. Chem. Soc. (1960), 82, 4367-4369). This compound (1.78 g, 10 mmol) was converted into 4-chloro-6-methylpyrrolo[3,4-c]pyridine-1 ,3- dione using phosphorus oxychloride (5.51 mL, 60 mmol), tetraethylammonium chloride (3.31 g, 20 mmol) and N,N-dimethylaniline (1.26 mL, 10 mmol) in acetonitrile (50 mL). This reaction mixture was heated at reflux for 4 h and then stirred at ambient temperature for 18 h. The mixture was evaporated to a residue which was purified by flash column chromatography. Elution with a mixture of n-heptane/EtOAc (3:2) provided the compound 4-chloro-6-methylpyrrolo[3,4-c]pyridine-1 ,3-dione as a foam (1.25 g, 63%). ¹H NMR (200 MHz; DMSO-d₆) δ 2.64 (3H, s, -CH₃), 7.76 (1 H, s, H-7), 11.71 (1 H. S. -NH).

ii) 6-Methyl-4-phenoxy-1 H-pyrrolo[3,4-c]pyridine-1 ,3(2H)-dione (Method A)

To dried phenol (0.19 g, 2.0 mmol) in dry DMF (10 mL) was added sodium hydride (80% in oil) (0.06 g, 2.0 mmol) and this solution was stirred at ambient temperature for 1 h. 4-Chloro-6-methylpyrrolo[3,4-c]pyridine-1 ,3-dione (0.39 g, 2.0 mmol) was added and this solution stirred at ambient temperature for 18 h. The mixture was evaporated to a residue which was purified by flash column chromatography. Elution with a mixture of n-heptane/EtOAc (4:1 ) provided the title compound 6-methyl-4- phenoxy-1 H-pyrrolo[3,4-c]pyridine-1 ,3(2H)-dione as a solid (0.11 g, 22%), mp 217- 218°C. ¹H NMR (400 MHz; DMSO-d₆) δ 2.43 (3H, s, -CH₃), 7.17 -7.46 (5H, m, Ar-H), 7.40 (1 H, s, 7-CH), 11.48 (1 H, s, -NH). HPLC retention time 24.27 min (gradient elution over 30 min; 20-80% acetonitrile/0.1 % TFA in water, 99.5% purity at 250 nm).

Example 2 (Method B)

6-Methyl-4-^-methoxy-phenoxyV1 H-pyrrolo[3.4- yridine-1.3(2HVdione

To 4-methoxyphenol (0.24 g, 1.92 mmol) in DMF (10 mL) was added 4A molecular sieves (1 g), and the resulting mixture was stirred for 18 h at ambient temperature. Sodium hydride 80% in oil (0.046 g,1.92 mmol) was added and the resulting mixture stirred at ambient temperature for 2 h. The commercially available 6-methyl-4- (methylsulphonyl)-1H-pyrrolo[3,4-c7pyridine-1 ,3-(2H)-dione (0.38 g, 1.60 mmol) was introduced, and the mixture was stirred at 60°C for 18 h. The reaction mixture was filtered and evaporated to a residue which was purified by flash column chromatography. Elution with a mixture of n-heptane/EtOAc (4:1 ) provided the title compound 6-methyl-4-(4-methoxy-phenoxy)-1 H-pyrrolo[3,4-c]pyridine-1 ,3(2H)-dione as a solid (0.135 g, 30%). ¹H NMR (400 MHz; DMSO-d₆) δ 2.42 (3H, s, -CH₃), 3.78 (3H, s, - OCH₃), 6.97 -7.12 (4H, m, Ar-H), 7.39 (1 H, s, 7-CH), 11.45 (1 H, s, -NH). HPLC re- tention time 18.03 min (gradient elution over 30 min; 20-80% acetonitrile/0.1 % TFA in water, 98.0% purity at 250 nm). Example 3

6-Methyl-4-(4-iodophenoxy)-1 H-pyrrolo[3.4-c]pyridine-1.3(2H)-dione

4-lodophenol (0.40 g, 1.8 mmol) was reacted with 6-methyl-4-(methylsulphonyl)-1 H- pyrrolo[3,4-c]pyridine-1 ,3-(2H)-dione (0.40 g, 1.5 mmol) following the same procedure as outlined in method B (example 2). The residue was purified by flash column chromatography, eluting with a mixture of n-heptane/EtOAc (4:1). This provided the title compound 6-methyl-4-(4-iodophenoxy)-1 H-pyrrolo[3,4-c]pyridine-1 ,3(2H)-dione as a solid (0.2 g, 53%), mp 261-262°C ¹H NMR (400 MHz; DMSO-d₆) δ 2.43 (3H, s, CH₃), 7.01 , 7.05, 7.77, 7.79 (4H, 4d, Ar-H), 7.45 (1 H, s, 7-CH), 11.48 (1 H, s, -NH). HPLC retention time 25.14 min (gradient elution over 30 min; 20-80% acetoni- trile/0.1 % TFA in water, 96.4% purity at 250 nm).

Example 4

6-Methyl-4-(3.4-dichlorophenoxy)-1 H-pyrrolo[3.4-c]pyridine-1.3(2H)-dione

3,4-Dichlorophenol (0.293 g, 1.8 mmol) was reacted with 6-methyl-4- methyIsulphonyl)-1 H-pyrrolo[3,4-c]pyridine-1 ,3-(2H)-dione (0.40 g, 1.5 mmol) follow- ing the same procedure as outlined in method B. The residue was purified by flash column chromatography, eluting with a mixture of n-heptane/EtOAc (6:1). This provided the title compound 6-methyl-4-(3,4-dichlorophenoxy)-1 H-pyrrolo[3,4-c]pyridine- 1 ,3(2H)-dione as a solid (0.08 g, 17%). ¹H NMR (400 MHz; DMSO-d₆) δ 2.46 (3H, s, - CH₃), 7.28,7.61 ,7.72, (3H, m, Ar-H), 7.48 (1 H, s, H-7), 11.54 (1 H, s, -NH). HPLC retention time 26.42 min (gradient elution over 30 min; 20-80% acetonitrile/0.1% TFA in water, 97.9% purity at 254 nm). C₁₄H₈N₂CI₂O₃ requires C, 52.40; H, 2.50; N, 8.67. Found: C, 52.21 ; H, 2.53; N, 8.42%.

Example 5

3-(6-Methyl-1.3(2H)-dioxo-1 H-pyrrolo[3.4-c]pyridin-4-yloxy) benzoic acid ethyl ester

3-Hydroxybenzoic acid ethyl ester (0.30 g, 1.8 mmol) was reacted with 6-methyl-4- (methylsulphonyl)-1 H-pyrrolo[3,4-c]pyridine-1 ,3-(2H)-dione (0.40 g, 1.5 mmol) following the same procedure as outlined in method B. The residue was purified by flash column chromatography, eluting with a mixture of n-heptane/EtOAc (1 :1 ). This provided the title compound 3-(6-methyl-1 ,3(2H)-dioxo-1 H-pyrrolo[3,4-c]pyridine-4- yloxy) benzoic acid ethyl ester as a solid (0.34 g, 69%). H NMR (400 MHz; DMSO- d₆) δ 1.34 (3H, t, -CH₃), 2.46 (3H, s, -CH₃), 4.34 (2H, q, -CH₂), 7.52, 7.62, 7.72, 7.86, (4H, m, Ar-H), 7.47 (1 H, s, H-7), 11.52 (1 H, s, -NH). HPLC retention time 22.02 min (gradient elution over 30 min; 20-80% acetonitrile/0.1% TFA in water, 97.3% purity at 254 nm). C₁₄H₈N₂CI₂O₃ requires C, 52.40; H, 2.50; N, 8.67. Found: C, 52.21 ; H, 2.53; N, 8.42%. Mass m/z 327 (m⁺). Example 6

3-(6-Methyl-1.3(2HVdioxo-1 H-pyrrolo[3.4-c]pyridin-4-yloxy) benzoic acid

3-(6-Methyl-1 ,3(2H)-dioxo-1H-pyrrolo[3,4-c]pyridine-4-yloxy) benzoic acid ethyl ester (Example 5) (0.196 g, 0.6 mmol) was dissolved in 1 N NaOH (10 mL). After stirring for 3 h at room temperature, the solution was^" acidified with 1 N HCI (15 mL) to pH 2-3, extracted with dichloromethane (3 x 50 mL). The combined organic layers were dried (MgSO₄) and evaporated to a residue which was stirred for 1 h with EtOH (10 mL). The product was collected by filtration to provide the title compound 3-(6-Methyl- 1 ,3(2H)-dioxo-1 H-pyrrolo[3,4-c]pyridine-4-yloxy) benzoic acid (0.145 g, 81 %) as a solid. ¹H NMR (400 MHz; DMSO-d₆) δ 2.33 (3H, s, -CH₃), 7.35-7.87 (4H, m, Ar-H), 7.32 (1 H, s, H-7). HPLC retention time 6.04 min (gradient elution over 30 min; 20-80% acetonitrile/0.1 % TFA in water, 73.5% purity at 254 nm).

Example 7

6-Methyl-4-( -methylphenoxy -1 H-pyrrolo[3.4-c]pyridine-1.3(2H)-dione

4-Methylphenol (0.195 g, 1.8 mmol) was reacted with 6-methyl-4-(methylsulphonyl)- 1 H-pyrrolo[3,4-c]pyridine-1 ,3-(2H)-dione (0.40 g, 1.5 mmol) following the same procedure as outlined in method B. The residue was purified by flash column chroma- tography, eluting with a mixture of n-heptane/EtOAc (9:1 ). This provided the title compound 6-methyl-4-(4-methylphenoxy)-1 H-pyrrolo[3,4-c]pyridine-1 ,3(2H)-dione as a solid (0.12 g, 30%). ¹H NMR (400 MHz; DMSO-d₆) δ 2.34 (3H, s, -CH₃), 2.42 (3H, s -CH₃), 7.07, (2H, d, Ar-H), 7.24, (2H, d, Ar-H), 7.40 (1 H, s, H-7), 11.47 (1 H, s, -NH). HPLC retention time 20.10 min (gradient elution over 30 min; 20-80% acetoni- trile/0.1 % TFA in water, 96.5% purity at 254 nm).

Example 8

4-(6-Methyl-1.3(2H)-dioxo-1 H-pyrrolo[3.4-c]pyridin-4-yloxy) benzoic acid ethyl ester

4-Hydroxybenzoic acid ethyl ester (0.40 g, 2.4 mmol) was reacted with 6-methyl-4- (methylsulphonyl)-l H-pyrrolo[3,4-c]pyridine-1 ,3-(2H)-dione (0.48 g, 2.0 mmol) following the same procedure as outlined in method B. The residue was purified by flash column chromatography, eluting with a mixture of n-heptane/EtOAc (9:1). This provided the title compound 4-(6-methyl-1 ,3(2H)-dioxo-1 H-pyrrolo[3,4-c]pyridin-4- yloxy) benzoic acid ethyl ester as a solid (0.16 g, 25%). ¹H NMR (400 MHz; DMSO- d₆) δ 1.34 (3H, t, -CH₃), 2.46 (3H, s, -CH₃), 4.34 (2H, q, -CH₂), 7.34 (2H, d, Ar-H), 7.50 (1 H, s, H-7), 8.03 (2H, d, Ar-H), 11.52 (1H, s, -NH). HPLC retention time 20.47 min (gradient elution over 30 min; 20-80% acetonitrile/0.1% TFA in water, 97.5% purity at 254 nm). C₁₇H₁₄N₂O₅ requires C, 62.57; H, 4.32; N, 8.58. Found: C, 62.23; H, 4.34; N, 8.27%.

Example 9

6-Methyl-4-(4-nitrophenoxyV1 H-pyrrolo[3.4-c]pyridine-1.3(^,2H')-dione

6-Methyl-4-phenoxy-1 H-pyrrolo[3,4-c]pyridine-1 ,3(2H)-dione (Example 1 ) (0.102 g, 0.4 mmol) was dissolved in cone H₂SO₄ (0.1 mL) and cooled to 0 °C A solution of cone H₂SO₄ (0.017 mL, 0.3 mmol) and cone. HNO₃ (0.017 mL, 0.4 mmol) was added dropwise over 10 min. The reaction mixture was stirred for 1 h at 0 °C and poured into water (10 mL). After stirring for 0.5 h the product was collected by filtration to provide the title compound 6-methyl-4-(4-nitrophenoxy)-1 H-pyrrolo[3,4-c]pyridine- 1 ,3(2H)-dione (0.015 g, 13%) as a solid. Mp: > 250 °C ¹H NMR (400 MHz; DMSO- d₆) δ 2.49 (3H, s, -CH₃), 7.47 (2H, m, Ar-H), 7.56 (1 H, s, H-7), 8.33 (2H, m, Ar-H). HPLC retention time 18.64 min (gradient elution over 30 min; 20-80% acetoni- trile/0.1 % TFA in water, 90.2% purity at 254 nm).

Example 10

4-(6-Methyl-1.3(2H)-dioxo-1 H-pyrrolo[3.4-c]pyridin-4-yloxy) benzoic acid benzyl ester

4-Hydroxybenzoic acid benzyl ester (0.51 g, 2.24 mmol) was reacted with 6-methyl- 4-(methylsulphonyl)-1 H-pyrrolo[3,4-c]pyridine-1 ,3-(2H)-dione (0.50 g, 1.86 mmol) following the same procedure as outlined in method B. The residue was purified by flash column chromatography, eluting with a mixture of n-heptane/EtOAc (9:1 ). This provided the title compound 4-(6-methyl-1 ,3(2H)-dioxo-1 H-pyrrolo[3,4-c]pyridin-4- yloxy) benzoic acid benzyl ester as a solid (0.41 g, 57%). ¹H NMR (400 MHz; CDCI₃) δ 2.53 (3H, s, -CH₃), 5.37 (2H, s, -CH₂), 7.25 -8.15 (10H, m, Ar-H and H-7). HPLC retention time 26.11 min (gradient elution over 30 min; 20-80% acetonitrile/0.1 % TFA in water, 95.3% purity at 254 nm). Mass m/z 389 (m⁺).

Example 11

4-(6-Methyl-1.3(2HVdioxo-1 H-pyrrolo[3.4-c]pyridin-4-yloxy benzoic acid

10% Palladium on carbon catalyst was added to a solution of 4-(6-methyl-1 ,3(2H)- dioxo-1 H-pyrrolo[3,4-c]pyridin-4-yloxy) benzoic acid benzyl ester (0.30 g, 7.7 mmol) (Example 10) in methanol (10 mL) and the reaction mixture was stirred under a hy- drogen atmosphere for 2 h. The mixture was filtered and evaporated to a residue which was added with a saturated solution of NaHCO₃ in H₂O (50 mL) and extracted with dichloromethane (3 x 50 mL). The aqueous layer was acidified to pH 1-2 with 1 N HCI (60 mL), and the product was collected by filtration to provide the title compound 4-(6-methyl-1 ,3(2H)-dioxo-1 H-pyrrolo[3,4-c]pyridine-4-yloxy) benzoic acid (0.03 g, 13%) as a solid. ¹H NMR (400 MHz; DMSO-d₆) δ 2.46 (3H, s, -CH₃), 7.25 (2H, d, Ar-H), 7.48 (1 H, s, H-7), 7.98 (2H, d, Ar-H). HPLC retention time 12.88 min (gradient elution over 30 min; 20-80% acetonitrile/0.1% TFA in water, 96.9% purity at 254 nm).

Example 12

6-Methyl-4-φhenylthioV1 H-pyrrolo[3.4-φyridine-1.3(2HVdione

Thiophenol (0.32 mL, 3.12 mmol) was reacted with sodium hydride 80% in oil (0.094 g, 3.12 mmol) and 4-chloro-6-methylpyrrolo[3,4-c]pyridine-1 ,3-dione (0.8 g, 2.6 mmol) following the same procedure as in method A. The residue was purified by flash column chromatography, eluting with a mixture of n-heptane/EtOAc (1 :1) to provide the title compound 6-methyl-4-(phenylthio)-1H-pyrrolo[3,4-c]pyridine-1 ,3(2H)- dione as a solid (0.3 g, 43%). ¹H NMR (300 MHz; DMSO-d₆) δ 2.40 (3H, s, -CH₃), 7.45-7.58 (5H, m, Ar-H), 11.55 (1 H, s, -NH). Mass m/z 271 (m⁺). HPLC retention time 21.83 min (gradient elution over 15 min; 5-90% acetonitrile/0.1 % TFA in water, 95.3% purity at 250 nm).

Example 13

6-Methyl-4-(2-thiophenylthioV1 H-pyrrolo[3.4-c]pyridine-1.3 2HVdione

2-Mercaptothiophene (0.28 g, 2.4 mmol) was reacted with sodium hydride 80% in oil (0.072 g, 2.4 mmol) and 4-chloro-6-methylpyrrolo[3,4-c]pyridine-1 ,3-dione (0.61 g, 3.0 mmol) following the same procedure as in method A. The residue was purified by flash column chromatography, eluting with a mixture of n-heptane/EtOAc (4:1 ). This provided the title compound 6-methyl-4-(2-thiophenylthio)-1H-pyrrolo[3,4-c]pyridine- 1 ,3(2H)-dione as a solid (0.28 g, 42%). ¹H NMR (400 MHz; DMSO-d₆) δ 2.47 (3H, s, CH₃ ), 7.19,7.37,7.89 (3H, m, -CH, thiophenyl), 7.45 (1 H, s, 7-CH), 11.57 (1 H, s, - NH). Mass m/z 277 (m⁺). HPLC retention time 22.47 min (gradient elution over 15 min; 5-90% acetonitrile/0.1 % TFA in water, 98.2% purity at 250 nm).

Example 14

6-Methyl-4-(4-fluorophenylthioV1 H-pyrrolo[3.4-c]pyridine-1.3(2HVriione

4-Fluorothiophenol (0.26 mL, 2.4 mmol) was reacted with 4-chloro-6- methylpyrrolo[3,4-c]pyridine-1 ,3-dione (0.315 g, 1.60 mmol) following the same pro- cedure as in method A. The residue was purified by flash column chromatography, eluting with a mixture of n-heptane/EtOAc (4:1 ) to provide the title compound 6- methyl-4-(4-fluorophenylthio)-1 H-pyrrolo[3,4-c]pyridine-1 ,3(2H)-dione as a solid (0.34 g, 74%). ¹H NMR (400 MHz; DMSO-d₆) δ 2.40 (3H, s, -CH₃), 7.32 (2H, m, Ar-H), 7.42 (1 H, s, H-7), 7.62 (2H, m, Ar-H), 11.56 (1 H, s, -NH). HPLC retention time 20.18 min (gradient elution over 30 min; 20-80% acetonitrile/0.1% TFA in water, 98.4% purity at 254 nm). Mass m/z 289 (m⁺)

Example 15

6-Methyl-4- 4-methoxyphenylthio)-1 H-pyrrolo[3.4-c1pyridine-1.3(2HVdione

4-Methoxythiophenol (0.356 g, 2.54 mmol) was reacted with sodium hydride 80% in oil (0.076 g, 2.54 mmol) and 4-chloro-6-methylpyrrolo[3,4-c]pyridine-1 ,3-dione (0.5 g, 2.54 mmol) following the same procedure as in method A. The residue was purified by flash column chromatography, eluting with EtOAc to provide the title compound 6- methyl-4-(4-methoxyphenylthio)-1 H-pyrrolo[3,4-c]pyridine-1 ,3(2H)-dione as a solid (0.577 g, 76%). ¹H NMR (300 MHz; DMSO-d₆) δ2.39 (3H, s, -CH₃), 3.79 (3H, s, -OCH₃), 7.02, 7.45 (4H, m, Ar-H), 7.38 (1H, s, 7-CH), 11.51 (1 H, s, -NH). Mass m/z 301 (m⁺). HPLC retention time 22.86 min (gradient elution over 15 min; 5-90% ace- tonitrile/0.1 % TFA in water, 96.6% purity at 250 nm).

Example 16

6-Methyl-4-[(4-acetamido)phenylthio]-1 H-pyrrolo[3.4-c]pyridine-1.3(2H)-dione

4-Acetamidothiophenol (0.424 g, 2.54 mmol) was reacted with sodium hydride 80% in oil (0.076 g, 2.54 mmol) and 4-chloro-6-methylpyrrolo[3,4-c]pyridine-1 ,3-dione (0.5 g, 2.54 mmol) following the same procedure as in method A. The residue was purified by flash column chromatography, eluting with EtOAc to provide the title com- pound 6-methyl-4-[(4-acetamido)phenylthio]-1 H-pyrrolo[3,4-c]pyridine-1 ,3(2H)-dione as a solid (0.296 g, 35%). ¹H NMR (300 MHz; DMSO-d₆) δ 2.08 (3H, s, -CH₃, acetamido), 2.39 (3H, s, -CH₃ ), 7.38 (1H, s, 7-CH), 7.48,7.69 (4H, m, Ar-H) 10.12 (1 H, s, -NH, acetamido), 11.52 (1 H, s, -NH). Mass m/z 328 (m⁺).

Example 17

NH,

6-Methyl-4-(2-aminophenylthio)-1 H-pyrrolo[3.4-c]pyridine-1.3(2H^')-dione

2-Aminothiophenol (0.38 g, 3.0 mmol) was reacted with sodium hydride 80% in oil (0.072 g, 3.0 mmol) and 4-chloro-6-methylpyrrolo[3,4-c]pyridine-1 ,3-dione (0.49 g, 2.5 mmol) following the same procedure as in method A. The residue was purified by flash column chromatography, eluting with a mixture of n-heptane/EtOAc (4:1 ) to provide the title compound 6-methyl-4-(2-aminophenylthio)-1 H-pyrroIo[3,4-c]pyridine- 1 ,3(2H)-dione as a solid (0.35 g, 50%), mp 176-177°C ¹H NMR (300 MHz; CDCI₃) δ 2.41 (3H, s, -CH₃), 5.19 (2H, s, -NH₂), 6.57, 6.78, 7.18, 7.27 (4H, m, Ar-H), 7.37 (1 H, s, 7-CH), 11.48 (1 H, s, -NH). Mass m/z 286 (m⁺).

Example 18

6-Methyl-4-methylthio-1 H-pyrrolo[3.4-c]pyridine-1.3(2HVdione

Sodium thiomethoxide (0.22 g, 3.12 mmol) was reacted with 4-chloro-6- methylpyrrolo[3,4-c]pyridine-1 ,3-dione (0.8 g, 4.07 mmol) in DMF and in the presence of molecular sieves (1 g, 3A). The reaction mixture was filtered and evaporated to a residue which was purified by flash column chromatography. Elution with a mixture of n-heptane/EtOAc (4:1 ) provided the title compound 6-methyl-4-methylthio-1 H- pyrrolo[3,4-c]pyridine-1 ,3(2H)-dione as a solid (0.02 g, 3.7%). ¹H NMR (400 MHz; DMSO-dg) δ 2.58 (3H, s, -SCH₃), 2.63 (3H, s, -CH₃), 7.38 (1 H, s, 7-CH), 11.40 (1 H, s, -NH). Mass m/z 209 (m⁺).

Example 19

4-Cyclohexylthio-6-methyl-1 H-pyrrolo[3.4-c]pyridine-1.3(2H)-dione

Cyclohexanethiol (0.295 g,2.54 mmol) was reacted with sodium hydride 80% in oil (0.076 g, 2.54 mmol) and 4-chloro-6-methylpyrrolo[3,4-c]pyridine-1 ,3-dione (0.5 g, 2.54 mmol) following the same procedure as in method A. The residue was purified by flash column chromatography, eluting with a mixture of n-heptane/EtOAc (4:1 ) to provide the title compound 4-cyclohexylthio-6-methyl-1 H-pyrrolo[3,4-c]pyridine- 1 ,3(2H)-dione as a solid (0.004 g). ¹H NMR (300 MHz; CDCI₃) δ 1.21-2.11 (10H, m, cyclohexyl), 2.68 (3H, s, -CH₃), 4.16 (1 H, m, cyclohexyl), 7.20 (1 H, s, 7-CH), 7.87 (1 H, s, -NH). HPLC retention time 23.82 min (gradient elution over 15 min; 5-90% acetonitrile/0.1 % TFA in water, 97.1 % purity at 250 nm).

Example 20

4-(1 -Ethyl-propylthio)-6-methyl-1 H-pyrrolo[3.4-c]pyridine-1.3(2H)-dione

Pentanethiol (0.189 g, 1.8 mmol) was reacted with sodium hydride 80% in oil (0.054 g, 1.8 mmol) and 6-methyl-4-(methylsulphonyl)-1 H-pyrrolo[3,4-c]pyridine-1 ,3-(2H)- dione (0.36 g, 1.5 mmol) following the same procedure as outlined in method B. The residue was purified by flash column chromatography, eluting with a mixture of n- heptane/EtOAc (2:1 ) to provide the title compound 4-(1-ethyl-propylthio)-6-methyl- 1 H-pyrrolo[3,4-c]pyridine-1 ,3(2H)-dione as a solid (0.033 g, 9%). Η NMR (400 MHz; DMSO-dg) δ 0.95-0.98 (6H, m, 2-CH_3, pentyl), 1.62-1.76 (4H, m, 2-CH₂, pentyl), 2.62 (3H, s, -CH₃), 4.07 (1 H, m, -CH, pentyl), 7.35 (1 H, s, 7-CH), 11.39 (1 H, s, -NH). Mass m/z 265 (m⁺). Example 21

(6-Methyl-1.3(2H)-dioxo-1 H-pyrrolo[3.4-c]pyridin-4-ylthio) acetic acid ethyl ester

Ethyl 2-mercaptoacetate (0.3 g, 2.5 mmol) was reacted with sodium hydride 80% in oil (0.075 g, 2.5 mmol) and 6-methyl-4-(methylsulphonyl)-1 H-pyrrolo[3,4-c]pyridine- 1 ,3-(2H)-dione (0.5 g, 2.1 mmol) following the same procedure as outlined in method B. The residue was purified by flash column chromatography, eluting with a mixture of n-heptane/EtOAc (2:1 ) to provide the title compound (6-methyl-1 ,3(2H)-dioxo-1 H- pyrrolo[3,4-c]pyridin-4-ylthio) acetic acid ethyl ester as a solid (0.454 g, 81%). H NMR (300 MHz; DMSO-d₆) δ 1.20 (3H, m, -CH_3, ethyl), 2.57 (3H, s, -CH₃), 4.07 (2H, s, -CH₂), 1.62-1.76 (2H, m, -CH₂, ethyl), 7.41 (1 H, s, 7-CH), 11.51 (1 H, s, -NH). HPLC retention time 21.10 min (gradient elution over 30 min; 20-80% acetoni- trile/0.1 % TFA in water, 97.8% purity at 250 nm).

Example 22

6-MethvI-4-(2-thiazolylthio)-1 H-pyιτolo[3.4-c]pyricline-1.3(2H)-dione 2-Mercaptothiazole (0.37 g, 3.12 mmol) was reacted with sodium hydride 80% in oil (0.09 g, 3.12 mmol) and 4-chloro-6-methylpyrrolo- [3,4-c]pyridine-1 ,3(2H)-dione (0.51 g, 2.6 mmol) following the same procedure as in method A. The residue was purified by flash column chromatography, eluting with a mixture of n-heptane/EtOAc (4:1 ) to provide the title compound 6-methyl-4-(2-thiazolylthio)-1 H-pyrrolo[3,4-c]pyridine-

1 ,3(2H)-dione as a solid (0.004 g). Η NMR (400 MHz; DMSO-d₆) δ 2.65 (3H, s, -CH₃), 7.58 (1 H, s, 7-CH), 7.96 (2H, m, -CH, thiazole), 11.69 (1 H, s, -NH). C^H^ S, requires C, 47.64; H, 2.54; N, 15.15. Found C, 47.54; H, 2.56; N, 14.79%.

Example 23

6-Methyl-4-phenyl-1 H-pyrrolo[3.4-c]pyridine-1 ,3(2H)-dione

Lithium (0.084 g, 12 mmol) was added to a solution of naphthalene (3.07 g, 24 mmol) in dry THF (10 mL), and the mixture was stirred at ambient temperature for 18 h. The resultant green solution was treated with 1 M zinc chloride in THF (6.6 mL) over 15 min. 4-lodo-6-methylpyrrolo[3,4-c]pyridine-1 ,3-dione (prepared by treating 4- chloro-6-methylpyrrolo[3,4-c]pyridine-1 ,3-dione with sodium iodide in acetone) (0.58 g, 2.0 mmol) was added, and the mixture was stirred for 4 h at ambient temperature. The mixture was filtered and the filtrate treated with iodobenzene (0.41 g, 2 mmol) and tetrakis(triphenylphosphine) palladium(O) (10 mg, 0.5%). The solution was stirred at ambient temperature for 72 h. The reaction mixture was quenched with a saturated NH₄CI solution (50 mL) and then extracted with dichloromethane (3 x 50 mL). The combined organic layers were dried (MgSO₄) and evaporated and the residue was purified by flash column chromatography, eluting with a mixture of n- heptane/EtOAc (2:1 ) to provide the title compound 6-methyl-4-phenyl-1 H-pyrrolo[3,4- c]pyridine-1 ,3(2H)-dione as a solid (0.01 g, 2%). ¹H NMR (400 MHz; DMSO-d₆) δ 2.71 (3H, s, -CH₃),7.49-7.91 (5H, m, Ar-H), 7.68 (1 H, s, 7-CH), 11.55 (1 H, s, -NH). Mass m/z 239 (m⁺).

The next 4 examples all use 4-(4-chlorophenylthio)-6-methyl-1 H-pyrrolo[3,4- c]pyridine-1 ,3(2H)-dione as a starting material which is commercially available.

Example 24

4-(4-Chlorophenylsulphinyl)-6-methyl-1 H-pyrrolo[3.4-c]pyridine-1.3(2H)-dione

4-(4-Chlorophenylthio)-6-methyl-1 H-pyrrolo[3,4-c]pyridine-1 ,3(2H)-dione (0.3 g, 1.0 mmol) dissolved in dichloromethane (10 mL) was treated with potassium peroxymonosulphate (1.54 g, 0.25 mmol) and montmorillonite K10 (20% water) (1.23 g). The reaction mixture was treated immediately with water (50 mL) and dichloromethane (40 mL), the organic layer separated and the aqueous phase extracted with dichloromethane (2 x 50 mL) . The combined organic layers were dried (MgSO₄) and evaporated and the residue was purified by flash column chromatography, eluting with a mixture of n-heptane/EtOAc (1 :4) to provide the title compound 4-(4-chlorophenylsulphinyl)-6-methyl-1 H-pyrrolo[3,4-c]pyridine-1 ,3(2H)- dione (0.09 g, 28%). ¹H NMR (400 MHz; DMSO-d₆) δ 2.69 (3H, s, -CH₃), 7.82 (1 H, s, - CH, purine), 7.60,7.75 (4H, m, Ar-H), 11.87 (1 H, s, -NH). HPLC retention time 13.55 min (gradient elution over 30 min; 20-80% acetonitrile/0.1 % TFA in water, 95% purity at 250 nm). Example 25

4-/4-Chlorophenylsulphonyπ-6-methyl-1 H-pyrrolo[3.4-c1pyridine-1.3C2HVdione

4-(4-Chlorophenylthio)-6-methyl-1 H-pyrrolo[3,4-c]pyridine-1 ,3(2H)-dione (0.3 g, 1.0 mmol) dissolved in dichloromethane (10 mL) was treated with potassium peroxymonosulphate (1.54 g, 0.25 mmol) and montmorillonite K10 (20% water) (1.23 g). The reaction mixture was stirred at ambient temperature for 72 h and then filtered and the filtrate was evaporated to half of its original volume. Methanol (30 mL) was added and the product crystallised out and was filtered to provide the title compound 4-(4-chlorophenylsulphonyl)-6-methyl-1 H-pyrrolo[3,4-c]pyridine-1 ,3(2H)-dione (0.18 g, 53%), mp 192-194°C ¹H NMR (400 MHz; DMSO-d₆) δ 2.63 (3H, s, -CH₃), 7.75, 8.02 (4H, m, Ar-H), 8.02 (1 H, s, -CH, purine), 11.87 (1 H, s, -NH). HPLC retention time 17.40 min (gradient elution over 30 min; 20-80% acetonitrile/0.1 % TFA in water, 95.4% purity at 250 nm).

Example 26

4-(4-ChlorophenylthioV2.6-dimethyl-1 H-pyrrolo[3.4-c]pyridine-1.3-dione To the commercially available 4-(4-chlorophenylthio)-6-methyl-pyrrolo[3,4-c]-pyridine- 1 ,3(2H)-dione (0.27 g, 0.9 mmol) in THF (10 mL) was added 2.5 M n-butyllithium in hexane (0.25 mL, 0.9 mmol). The mixture was stirred at ambient temperature for 1 h. lodomethane (0.06 mL, 0.9 mmol) was added and the resultant mixture was stirred at the same temperature for 18h. The reaction mixture was filtered and evaporated to a residue which was purified by flash column chromatography. Elution with a mixture of n-heptane/EtOAc (4:1 ) provided the title compound 4-(4-chlorophenylthio)-2,6- dimethyl-1 H-pyrrolo[3,4-cjpyridine-1 ,3-dione as a solid (0.07 g, 24%). ¹H NMR (400 MHz; DMSO-dg) δ 2.42 (3H, s, -CH₃), 3.03 (3H, s, N-CH₃) 7.49 (1 H, s, -CH, purine), 7.52-7.60 (4H, m, Ar-H).

Example 27

5-(4-ChlorophenylthioV7-methyl-1 H-pyrido[3.4-c]pyridazine-1.4(2.3H)-dione

The commercially available 4-(4-chioro-phenylthio)-6-methyl-pyrrolo[3,4-c]-pyridine- 1 ,3(2H)-dione (0.53 g, 1.75 mmol) dissolved in ethanol (30 mL) was treated with hy- drazine hydrate (0.17 mL, 3.50 mmol) and stirred at ambient temperature for 18h. The crude product was filtered off and recrystallised from ethanol (30 mL) to provide the title compound 5-(4-chlorophenylthio)-7-methyl-1 H-pyrido[3,4-c]pyridazine- 1 ,4(2,3H)-dione (0.05 g, 9%). ¹H NMR (400 MHz; DMSO-d₆) δ 2.30 (3H, s, -CH₃), 7.13 (1 H, s, -CH, purine), 7.42 (4H, m, Ar-H), 9.41 ,9.51 (2H, d, 2x -NH). Example 28

6-tetf-Butyl-4-phenoxy-1 H-pyrrolo[3.4-c]pyridine-1.3(2H)-dione

4-Chloro-6-te/t-butylpyrrolo[3,4-c]pyridine-1 ,3-dione (0.20 g, 0.85 mmol) prepared using the published route (Dickinson, CL^'., J. Amer. Chem. Soc, 1960, 82, 4367- 4369) was reacted with phenol (0.12 g, 1.28 mmol) following the same procedure as in method A. The residue was purified by flash column chromatography, eluting with a mixture of n-heptane/EtOAc (4:1 ). This provided the title compound 6-terf-butyl-4- phenoxy-1H-pyrrolo[3,4-c]pyridine-1 ,3(2H)-dione as a solid (0.13 g, 52%). ¹H NMR (400 MHz; DMSO-d₆) δ 1.17 (9H, s, -CH₃), 7.20-7.48 (6H, m, 5H, Ar-H, 1 H, H-7), 11.50 (1 H, s, -NH). HPLC retention time 27.95 min (gradient elution over 30 min; 20-80% acetonitrile/0.1 % TFA in water, 95.0% purity at 254 nm).

Example 29

Biological activity

The ability of the present compounds to stimulate glucose incorporation into lipid was determined by the method of Moody et al. (Moody et al. (1974) Horm. Metab. Res. 6, 12-16), with slight modifications. Primary mouse adipocytes were prepared by collagenase treatment of epididymal fatpads for 1.5 h at 36 °C (25 mM Hepes, 4% human serum albumin, 1 mM glucose, 800 U/mL collagenase Type 1 in Krebs buffer, pH 7.4), followed by filtration through gauze and two washes by gentle centrifugation. The adipocytes were incubated with or without test compound at a submaximal con- centration of insulin for 2 h at 36 °C in the presence of D-(3-³H)-glucose, and the radioactivity incorporated into the lipid was determined by subsequent addition of an organic scintillation cocktail and counting. An increase in radioactivity incorporated in the presence of test compound reflects an increase in insulin sensitivity.

The maximum increase in insulin sensitivity achieved in the dose range of 0.3-100 μM of test compound, normalised to the full insulin dose response (100%) was determined. Test results for compounds showing an increase in insulin sensitivity by more than 5% are given in Table 1 below.

Table 1

Biological effect of the compounds according to the invention. Results are given as the maximum increase in insulin sensitivity achieved in the dose range 0.3-100 μM of compound, normalised to the full insulin dose response (100%).

From the foregoing, it will be appreciated that, although specific embodiments of the invention have been described herein for the purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention as defined by the appended claims.

Claims

1. A pyrimidine or pyridine derivative of the general formula I

wherein

X represents

NR⁴ wherein R⁴ represents hydrogen or C^-alkyl which is optionally substituted with halogen, hydroxy, amino, mercapto,

(NR⁴)₂ wherein R⁴ which may be the same or different have the above meanings;

Y represents N or CR⁵ wherein R⁵ is

hydrogen, halogen,

C|_₆-alkyl, C₂.₆-alkenyl or C₂.₆-alkynyl which are optionally substituted with halogen, hydroxy, amino, mercapto,

or di-

C₃.₈-cycloalkyl, aryl or heteroaryl which are optionally substituted with C^-alkyl, halogen, hydroxy, amino, mercapto,

C_Lg-alkylamino or di-C_Lg-alkylamino; R¹ represents

hydrogen, halogen, C^-alkoxy, C^-alkylthio or C_Lg-alkylamino,

C₂.₆-alkenyl or C₂.₆-alkynyl which are optionally substituted with halogen, hydroxy, amino, mercapto,

C,.₆-alkylamino or di- C^-alkylamino, or

C₃.₈-cycloalkyl, aryl or heteroaryl which are optionally substituted with C^-alkyl, halogen, hydroxy, amino, mercapto,

or

Z represents O, S, SO or SO₂; and

R² represents

C₂.₆-alkenyl or C₂.₆-alkynyl which are optionally substituted with halogen, hydroxy, C^-alkoxy, amino, nitro, carboxy, C^-alkylamino, di-C^- alkylamino,

aralkyloxycarbonyl, mercapto, C^-alkylthio, C^-cycloalkyl, aryl or heteroaryl, where

- the aryl moiety of the C^-aralkyloxycarbonyl group, the C₃.₈-cycloalkyl, aryl and heteroaryl groups optionally are substituted with

halogen, hy- droxy, amino, mercapto,

alkylamino, or

C^-cycloalkyl, aryl or heteroaryl which are optionally substituted with C^-alky!, halogen, hydroxy,

alkylamino,

aralkyloxycarbonyl, mercapto or C_Lg-alkylthio, where - the aryl moiety of the

group optionally is substituted with C^-alkyl, halogen, hydroxy, amino, mercapto, C^-alkoxy, C_Lg-alkylthio, C,_g-alkylamino or di-C,.₆-alkylamino and

- the group optionally is substituted with halogen, hydroxy, amino, mercapto,

or

Z and R² taken together may represent C₃^-cycloalkyl, aryl or heteroaryl which are optionally substituted with C^-alkyl, halogen, hydroxy, C^-alkoxy, amino, nitro, carboxy, C^-alkylamino, di-C,.₆-alkylamino, C^-alkanoylamino, C^- alkanoyl, C^-alkoxycarbonyl, C^-aralkyloxycarbonyl, mercapto or C^-alkylthio;

with the proviso that

when X represents NH, Y represents CH, R¹ represents methyl and Z represents S, R² must not be p-chlorophenyl; and

when X represents NH or NCH₃, Y represents CH, R¹ represents methyl and Z represents O, R² must not be methyl;

as well as a pharmaceutically acceptable salt thereof or any optical or geometric isomer or tautomeric form thereof including mixtures of these.

2. A pyridine derivative according to claim 1 wherein

X represents NR⁴ wherein R⁴ is as defined in claim 1 ;

Y represents CR⁵ wherein R⁵ is as defined in claim 1 ;

R¹ represents a

group optionally substituted as defined in claim 1 ;

Z represents S or O; and R² represents

optionally substituted as defined in claim 1 ;

C₂_g-alkenyl optionally substituted as defined in claim 1 ;

C₂.₆-alkynyl optionally substituted as defined in claim 1 ;

C₃.₈-cycloalkyl optionally substituted as defined in claim 1 ;

aryl optionally substituted as defined in claim 1 ; or

heteroaryl optionally substituted as defined in claim 1.

3. A pyridine derivative according to claim 2 wherein

X represents NH;

Y represents CH;

R¹ represents C^-alkyl, and

R² represents

optionally substituted as defined in claim 1 ;

C₂.₆-alkenyl optionally substituted as defined in claim 1 ;

C₂.g-alkynyl optionally substituted as defined in claim 1 ; phenyl optionally substituted as defined in claim 1 ;

cyclohexyl optionally substituted as defined in claim 1 ; or

furyl, thienyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl or pyrrolyl which are optionally substituted as defined in claim 1.

4. A pyridine derivative according to claim 3 wherein R¹ represents methyl.

5. A pyridine derivative according to claim 3 or 4 wherein

R² represents

or amino;

cyclohexyl optionally substituted with halogen, C^-alkoxy, amino or C,.₆-alkyl; or

phenyl optionally substituted as defined in claim 1.

6. A pyridine derivative according to claim 5 wherein

R² represents

C^-alkyl optionally substituted with halogen, C^-alkoxy or amino;

cyclohexyl optionally substituted with halogen,

or

phenyl optionally substituted with halogen,

7. A pyrimidine or pyridine derivative according to the formula I'

wherein

X represents

NR⁴ wherein R⁴ represents hydrogen or C^-alkyl which is optionally substituted with halogen, hydroxy, amino, mercapto, C^-alkoxy, C^-alkylthio,

(NR⁴)₂ wherein R⁴ which may be the same or different have the above mean- ings;

Y represents N or CR⁵ wherein R⁵ is

hydrogen, halogen,

or C₂.₆-alkynyl which are optionally substituted with halogen, hydroxy, amino, mercapto, C^-alkoxy, C^-alkylthio, C^-alkylamino or di-

C₃.₈-cycloalkyl, aryl or heteroaryl which are optionally substituted with C^-alkyl, halogen, hydroxy, amino, mercapto,

alkylamino; R represents

hydrogen, halogen, C^-alkoxy, C^-alkylthio or C^-alkylamino,

C₂.₆-alkenyl or C₂.₆-alkynyl which are optionally substituted with halogen, hydroxy, amino, mercapto,

or di-

C₃.₈-cycloalkyl, aryl or heteroaryl which are optionally substituted with C,_.g-alkyl, halogen, hydroxy, amino, mercapto,

or

Z represents O, S, SO or SO₂; and

R² represents

C₂.₆-alkenyl or C₂.₆-alkynyl which are optionally substituted with halogen, hydroxy,

amino, nitro, carboxy,

di-C,_.6- alkylamino,

aralkyloxycarbonyl, mercapto, C^-alkylthio, C^-cycloalkyl, aryl or heteroaryl, where

- the aryl moiety of the C^g-aralkyloxycarbonyl group, the C₃_g-cycloalkyl, aryl and heteroaryl groups optionally are substituted with

halogen, hy- droxy, amino, mercapto,

C,.g-alkylthio, C_Lg-alkylamino or di-

C_M-cycloalkyl, aryl or heteroaryl which are optionally substituted with C^-alkyl, halogen, hydroxy,

alkylamino, C_Lg-alkanoylamino,

C,_.g- aralkyloxycarbonyl, mercapto or

where - the aryl moiety of the

group optionally is substituted with

- the group optionally is substituted with halogen, hydroxy, amino, mercapto,

C_Lg-alkylamino or

or

Z and R² taken together may represent C₃.₈-cycloalkyl, aryl or heteroaryl which are optionally substituted with C^-alkyl, halogen, hydroxy, C^-alkoxy, amino, nitro, carboxy,

alkanoyl,

mercapto or

as well as a pharmaceutically acceptable salt thereof or any optical or geometric isomer or tautomeric form thereof including mixtures of these for use as a medicament.

8. A compound of the formula I' as defined in claim 7

wherein

X, Y and R are as defined for formula I';

Z represents O; and

R² represents

C₂.₆-alkenyl or C₂.₆-alkynyl which are optionally substituted with halogen, hydroxy,

C_Lg-alkanoylamino,

mercapto, C,.₆-alkylthio, C₃.₈-cycloalkyl, aryl or heteroaryl, where - the aryl moiety of the C^-aralkyloxycarbonyl group, the C^-cycloalkyl, aryl and heteroaryl groups optionally are substituted with C^-alkyl, halogen, hydroxy, amino, mercapto,

or di-

C₃.₈-cycloalkyl, aryl or heteroaryl which are optionally substituted with C^-alkyl, halogen, hydroxy, C^-alkoxy, amino, nitro, carboxy, C^-alkylamino, di-C^- alkylamino,

aralkyloxycarbonyl, mercapto or C^-alkylthio, where - the aryl moiety of the C,.e-aralkyloxycarbonyl group optionally is substituted with C-.g-alkyl, halogen, hydroxy, amino, mercapto,

- the group optionally is substituted with halogen, hydroxy, amino, mercapto,

as well as a pharmaceutically acceptable salt thereof or any optical or geometric isomer or tautomeric form thereof including mixtures of these.

9. A compound of the formula I' as defined in claim 7 wherein

X, Y and R¹ are as defined for formula I';

Z represents S; and

R² represents

C₂.₆-alkenyl or C₂.₆-alkynyl which are optionally substituted with halogen, hydroxy,

amino, nitro, carboxy,

alkylamino, C_Lg-alkanoylamino, C,.₆-alkanoyl, C^-alkoxycarbonyl, C^- aralkyloxycarbonyl, mercapto, C_Lg-alkylthio, C^-cycloalkyl, aryl or heteroaryl, where - the aryl moiety of the C^g-aralkyloxycarbonyl group, the C_3.8-cycloalkyl, aryl and heteroaryl groups optionally are substituted with C^-alkyl, halogen, hydroxy, amino, mercapto,

or di- C^-alkylamino, or

C₃.₈-cycloalkyl or heteroaryl which are optionally substituted with C^-alkyl, halogen, hydroxy,

amino, nitro, carboxy, C_Lg-alkylamino,

mercapto or

where - the aryl moiety of the C^-aralkyloxycarbonyl group optionally is substituted with

- the group optionally is substituted with halogen, hydroxy, amino, mercapto,

C_Lg-alkylamino or di-C_Lg-alkylamino, or

aryl which is optionally substituted with C^-alkyl, iodo, bromo, fluoro, meta- chloro, ortho-chloro, di-chloro, tri-chloro, hydroxy, C^-alkoxy, amino, nitro, carboxy,

mercapto or

where

- the aryl moiety of the

group optionally is substituted with

C_Lg-alkylamino or

and

- the group optionally is substituted with halogen, hydroxy, amino, mercapto,

or di-C_Lg-alkylamino.

as well as a pharmaceutically acceptable salt thereof or any optical or geometric isomer or tautomeric form thereof including mixtures of these.

10. A compound of the formula I' as defined in claim 7 wherein X represents

NR⁴ wherein R⁴ represents hydrogen or C^-alkyl which is optionally substituted with halogen, hydroxy, amino, mercapto, C^-alkoxy, C^-alkylthio,

(NR⁴)₂ wherein R⁴ which may be the same or different have the above meanings;

Y represents N or CR⁵ wherein R⁵ is

hydrogen, halogen,

C₂.₆-alkenyl or C₂.₆-alkynyl which are optionally substituted with halo- gen, hydroxy, amino, mercapto,

C_Lg-alkylthio,

or di-

C^-cycloalkyl, aryl or heteroaryl which are optionally substituted with C^-alkyl, halogen, hydroxy, amino, mercapto,

alkylamino;

R¹ represents

hydrogen, halogen, C,.₆-alkoxy,

C₂.₆-alkenyl or C₂.₆-alkynyl which are optionally substituted with halogen, hydroxy, amino, mercapto,

or di-

C₃-₈-cycloalkyl, aryl or heteroaryl which are optionally substituted with C^-alkyl, halogen, hydroxy, amino, mercapto, C^-alkoxy, C^-alkylthio, C_Lg-alkylamino or

Z represents SO or SO₂; and

R² represents

C₂.₆-alkenyl or C₂.₆-alkynyl which are optionally substituted with halo- gen, hydroxy,

amino, nitro, carboxy,

mercapto, C-,.₆-alkylthio, C₃.₈-cycloalkyl, aryl or heteroaryl, where

- the aryl moiety of the C,.₆-aralkyloxycarbonyl group, the C^-cycloalkyl, aryl and heteroaryl groups optionally are substituted with C,.₆-alkyl, halogen, hydroxy, amino, mercapto,

or di-

C₃.₈-cycloalkyl, aryl or heteroaryl which are optionally substituted with C^-alkyl, halogen, hydroxy,

mercapto or

where

- the aryl moiety of the C^-aralkyloxycarbonyl group optionally is substituted with

halogen, hydroxy, amino, mercapto,

C^-alkylamino or di-C^-alkylamino and

- the C,_₆-alkyl group optionally is substituted with halogen, hydroxy, amino, mercapto,

or

Z and R² taken together may represent C₃^-cycloalkyl, aryl or heteroaryl which are optionally substituted with

amino, nitro, carboxy,

alkanoyl, C^-alkoxycarbonyl, C^-aralkyloxycarbonyl, mercapto or C^_g-alkylthio;

as well as a pharmaceutically acceptable salt thereof or any optical or geometric isomer or tautomeric form thereof including mixtures of these.

11. A pharmaceutical composition comprising, as an active ingredient, at least one compound as defined in any one of the claims 1 to 10 together with one or more pharmaceutically acceptable carriers or excipients.

12. A pharmaceutical composition according to claim 11 in unit dosage form, comprising from about 0.05 mg to about 000 mg, preferably from about 0.1 mg to about 500 mg and especially preferred from about 0.5 mg to about 200 mg of the compound as defined in any one of the claims 1 to 10.

13. Use of a compound as defined in any one of the claims 1 to 10 for the preparation of a medicament for the treatment and/or prevention of disorders where a reduction of the blood glucose is beneficial.

14. Use of a compound as defined in any one of the claims 1 to 10 for the preparation of a medicament for the treatment and/or prevention of disorders where a stimulation of the blood glucose uptake into muscle and fat cells is beneficial.

15. Use of a compound as defined in any one of the claims 1 to 10 for the prepara- tion of a medicament for the treatment and/or prevention of disorders involving elevated plasma blood glucose.

16. Use of a compound as defined in any one of the claims 1 to 10 for the preparation of a medicament for the treatment and/or prevention of non-insulin dependent diabetes mellitus (NIDDM).

17. A method for the treatment of disorders in which a reduction of the blood glucose is beneficial the method comprising administering to a subject in need thereof an effective amount of a compound as defined in any one of the claims 1 to 10 or a pharmaceutical composition according to any one of the claims 11 or 12.

18. The method according to claim 14 wherein the effective amount of the compound as defined in any one of the claims 1 to 10 is in the range of from about 0.05 mg to about 2000 mg, preferably from about 0.1 mg to about 1000 mg and especially preferred from about 0.5 mg to about 500 mg per day.