HK1081965B

HK1081965B - Pyridopyrimidinone compounds, method for production thereof and medicaments comprising the same

Info

Publication number: HK1081965B
Application number: HK06102331.8A
Authority: HK
Inventors: Sylvain Rault; Jean-Charles Lancelot; Marina Kopp; Daniel-Henri Caignard; Bruno Pfeiffer; Pierre Renard
Original assignee: Les Laboratoires Servier
Priority date: 2002-11-05
Filing date: 2003-11-04
Publication date: 2007-10-26

Description

Pyridopyrimidinone compounds, process for their preparation and medicaments containing them

no marking

The present invention relates to novel pyridopyrimidinone compounds, processes for their preparation and pharmaceutical compositions containing them.

The compounds of the invention are novel and have valuable modulating properties on a group of kinases, making them useful in the treatment of many types of disorders, among which mention may be made, without implying any limitation: cancer, joint disease, diabetes, obesity, hypertension, etc. Furthermore, they are completely non-toxic. To the best of our knowledge, this class of compounds is entirely new and the activity we have found in them has not been described for structurally closed compounds.

More particularly, the present invention relates to compounds of formula (I), their enantiomers, diastereomers, tautomers and addition salts thereof with a pharmaceutically acceptable acid or base:

wherein:

R₁and R₂Identical or different, represents a hydrogen atom or an alkyl group, or forms, together with the nitrogen atom bearing them, a heterocycle;

R₃represents a halogen atom, an alkoxy group, an optionally substituted aryl group or a group NR'₁R’₂Wherein R'₁And R'₂Identical or different, represent a hydrogen atom or an alkyl group or form, together with the nitrogen atom bearing them, a heterocycle;

R₄represents a hydrogen atom or a group NR "₁R”₂Wherein R "₁And R "₂The same or different, represent a hydrogen atomOr alkyl or together with the nitrogen atom bearing them form a heterocyclic ring;

it should be understood that:

the term "alkyl" denotes a straight or branched hydrocarbon chain containing from 1 to 8 carbon atoms;

the term "alkoxy" denotes an alkyl-oxy group, wherein the alkyl chain is linear or branched and contains 1 to 8 carbon atoms;

-the term "aryl" denotes phenyl or naphthyl;

the term "heterocycle" denotes a monocyclic or bicyclic ring system, the radical containing from 5 to 11 carbon atoms and being other than bonded to R₁R₂、R’₁R’₂Or R'₁R”₂In addition to the nitrogen atom(s) of (a), the system may also contain one or two additional heteroatoms selected from oxygen, sulfur and nitrogen, said heterocyclic system possibly being substituted by one, two or three alkyl groups;

the term "substituted" in relation to aryl means that the phenyl or naphthyl group is substituted by one, two or three identical or different radicals chosen from halogen atoms and alkyl, alkoxy, polyhaloalkyl and hydroxyl, polyhaloalkyl being understood as a straight or branched carbon chain containing from 1 to 3 carbon atoms and from 1 to 7 halogen atoms.

Among the pharmaceutically acceptable acids, which may be mentioned without implying any limitation, are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, methanesulfonic acid, camphoric acid and the like.

Among the pharmaceutically acceptable bases, sodium hydroxide, potassium hydroxide, triethylamine and the like may be mentioned without implying any limitation.

A preferred embodiment of the present invention relates to compounds of formula (I'):

their enantiomers, diastereomers, tautomers and their addition salts with a pharmaceutically acceptable acid or base.

Another preferred embodiment of the present invention relates to the compounds in which NR is₁R₂Represents NH₂Compounds of the group di-n-propylamino or morpholinyl, their enantiomers, diastereomers, tautomers and addition salts thereof with a pharmaceutically acceptable acid or base.

Preferred compounds of the invention are those wherein R is₃Compounds representing 3, 4-dimethoxyphenyl, 3, 5-dimethylmorpholinyl, thiomorpholinyl, aza * yl, perhydroquinolinyl or pyrrolidinyl or a chlorine atom, their enantiomers, diastereomers, tautomers and addition salts thereof with a pharmaceutically acceptable acid or base.

Another preferred embodiment of the present invention relates to the compounds in which R is₄Compounds representing a hydrogen atom or a morpholinyl or aza * group, their enantiomers, diastereomers, tautomers and addition salts thereof with a pharmaceutically acceptable acid or base.

Among the preferred compounds of the invention, mention may be made of:

2- (dipropylamino) -8- (4-thiomorpholinyl) pyrido [3, 4-d ] pyrimidin-4 (3H) -one,

8- (1-azacyclooctyl) (azocanyl)) -2- (dipropylamino) pyrido [3, 4-d ] pyrimidin-4 (3H) -one,

8- ((4a α, 8a α) -octahydro-1- (2H) -quinolinyl) -2- (dipropylamino) pyrido [3, 4-d ] pyrimidin-4 (3H) -one, 8- ((4a β, 8a α) -octahydro-1- (2H) quinolinyl) -2- (dipropylamino) pyrido [3, 4-d ] pyrimidin-4 (3H) -one, 6, 8-bis (1-azepanyl) -2- (dipropylamino) pyrido [3, 4-d ] pyrimidin-4 (3H) -one,

8- (1-azepanyl) -2- (dipropylamino) -6- (4-morpholinyl) pyrido [3, 4-d ] pyrimidin-4 (3H) -one,

8- (1-azepanyl) -2, 6-bis (4-morpholinyl) pyrido [3, 4-d ] pyrimidin-4 (3H) -one,

2-amino-8- [ (3 α, 5 β) -3, 5-dimethylmorpholinyl ] pyrido [3, 4-d ] pyrimidin-4 (3H) -one,

2-amino-8- [ (3 α, 5 α) -3, 5-dimethylmorpholinyl ] pyrido [3, 4-d ] pyrimidin-4 (3H) -one,

8- [ (3. alpha., 5. beta) -3, 5-dimethylmorpholinyl ] -2- (dipropylamino) pyrido [3, 4-d ] pyrimidin-4 (3H) -one,

8- [ (3 α, 5 α) -3, 5-dimethylmorpholinyl ] -2- (dipropylamino) pyrido [3, 4-d ] pyrimidin-4 (3H) -one,

8- [ (3 α, 5 α) -3, 5-dimethylmorpholinyl ] -2- (4-morpholinyl) pyrido [3, 4-d ] pyrimidin-4 (3H) -one,

2-amino-8- (1-azepanyl) -6- (4-morpholinyl) pyrido [3, 4-d ] pyrimidin-4 (3H) -one,

8-chloro-2- (dipropylamino) pyrido [3, 4-d ] pyrimidin-4 (3H) -one,

2- (dipropylamino) -8- (1-pyrrolidinyl) pyrido [3, 4-d ] pyrimidin-4 (3H) -one, and

8- (3, 4-dimethoxyphenyl) -2- (dipropylamino) pyrido [3, 4-d ] pyrimidin-4 (3H) -one,

their tautomers and their addition salts with pharmaceutically acceptable acids.

The invention also relates to a process for the preparation of a compound of formula (I), which process is characterized in that: using a compound of formula (II) as a starting material,

wherein R is₃And R₄As defined in formula (I)In the meaning of,

condensing a compound of formula (II) with a compound of formula (III),

S＝C＝N-C(O)OR₂₀ (III)

wherein R is₂₀Represents an alkyl group or an aryl-alkyl group,

to generate the compound shown in the formula (IV),

wherein R is₃、R₄And R₂₀As defined above, in the above-mentioned manner,

condensing the compound of formula (IV) with an amine (V) in the presence of a metal salt,

HNR₁R₂ (V)

wherein R is₁And R₂As defined in formula (I),

to generate the compound shown in the formula (I),

the compounds of formula (I) may be purified, where appropriate, according to conventional purification methods;

-separating the compound of formula (I) into its stereoisomers, if appropriate according to conventional separation techniques;

-if desired, converting the compound of formula (I) into its addition salts with a pharmaceutically acceptable acid or base. It should be understood that:

protection of the amino or alkylamino group of the starting reagent (II) and subsequent deprotection for synthesis after condensation, whenever deemed appropriate during the above process;

the reagents (II) are described in the literature or are prepared according to known methods described in the literature.

The compounds of the invention have been studied with respect to a group of kinases for which they show excellent activity. This activity is usually specific for a particular type of kinase, which varies with the structure of the compound of formula (I).

Depending on the type of kinase for which the compounds of the invention are active, it is expected that the compounds of the invention will have excellent activity: various types of cancer, metabolic diseases, more particularly the treatment or prevention of hyperglycemia, dyslipidemia such as hypercholesterolemia and hyperlipidemia, as well as the treatment of non-insulin dependent type II diabetes mellitus, obesity and diabetic complications, diabetic complications particularly in the cardiovascular field, or inflammatory diseases such as arthrosis, or cardiovascular diseases not associated with diabetes such as arterial hypertension. Moreover, the fact that the compounds of the invention are completely non-toxic makes them of undeniable value for therapeutic use.

The present invention also relates to pharmaceutical compositions comprising as active ingredient at least one compound of formula (I), alone or in combination with one or more inert, non-toxic excipients or carriers.

Among the pharmaceutical compositions according to the invention, mention may be made more particularly of those suitable for oral, parenteral and nasal administration, such as tablets or dragees, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels and the like.

The effective dosage will vary depending upon the age and weight of the patient, the nature and severity of the condition, and the route of administration, which may be oral, nasal, rectal or parenteral. Generally, the unit dose is in the range of 0.01 to 500mg per 24 hours, and the treatment is carried out in 1 to 3 divided administrations.

The following examples illustrate the invention without limiting it in any way. The structure of the compounds has been determined by conventional spectroscopic and spectroscopic techniques.

The starting materials used are known products or are prepared according to known methods.

A (4a α, 8a α) compound is understood to mean a compound in which the relevant ring junction is in the cis configuration.

A (3 α, 5 α) compound is understood to mean a compound in which the relevant ring junction is in the cis configuration.

A (4a β, 8a α) compound is understood to mean a compound in which the relevant ring junction is in the trans configuration.

A (3 α, 5 β) compound is understood to mean a compound in which the relevant ring junction is in the trans configuration.

Example 1:

8- (1-azacyclooctyl) -2- (dipropylamino) pyrido [3, 4-d ] pyrimidin-4 (3H) -one

A mixture of 0.02mol (4.10g) of 3-amino-2-azacyclooctylpyridine and 0.02mol of ethoxycarbonyl isothiocyanate is stirred in 100ml of DMF at room temperature for 3 hours, by which thiourea of the formula (IV) is obtained, which does not have to be isolated. The solution is cooled to 0 ℃ and saturated with 2.5 equivalents of di-n-propylamine, 0.02mol of mercuric chloride being added; at the end of 15 minutes the ice bath was removed and the mixture was stirred at room temperature for 3 hours (a black precipitate due to mercury sulfide formation was still visible). After addition of 150ml of ethyl acetate, the solution is filtered through kieselguhr (Celite) and the solvent is distilled off under reduced pressure. The crude N-ethoxycarbonylguanidine thus obtained was again dissolved in 50ml of DMF and heated under reflux for 2 hours. After filtering the hot solution to remove the final residual mercury salt, the DMF was distilled off under reduced pressure. The solid thus obtained is charged with a minimum amount of acetonitrile, filtered off with suction through a glass filter and then recrystallized from acetonitrile.

Melting point: 172 deg.C

Example 2:

8- (4-Thiomolinyl) -2- (dipropylamino) pyrido [3, 4-d ] pyrimidin-4 (3H) -one

Following the procedure as in example 1, but substituting 3-amino-2- (4-thiomorpholinyl) pyridine for 3-amino-2-azacyclooctylpyridine, the title compound was obtained.

Melting point: 226 ℃ is prepared.

Example 3

8- ((4a alpha, 8a alpha) -octahydro-1 (2H) -quinolinyl) -2- (dipropylamino) pyrido [3, 4-d ] pyrimidin-4 (3H) -one

Following the procedure as in example 1, but substituting 2- ((4a α, 8a α) -octahydro-1 (2H) -quinolinyl) -3-pyridylamine for 3-amino-2-azacyclooctylpyridine, the title compound was obtained.

Melting point: 215 ℃ is adopted.

Example 4

8- ((4a beta, 8a alpha) -octahydro-1 (2H) -quinolinyl) -2- (dipropylamino) pyrido [3, 4-d ] pyrimidin-4 (3H) -one

Following the procedure as in example 1, but substituting 2- ((4a β, 8a α) -octahydro-1- (2H) -quinolinyl) -3-pyridylamine for 3-amino-2-azacyclooctylpyridine, the title compound was obtained.

Melting point: 225 ℃ is adopted.

Example 5

6, 8-bis (1-azepanyl) -2- (dipropylamino) pyrido [3, 4-d ] pyrimidin-4 (3H) -one

Following the procedure as in example 1, but substituting 3-amino-2, 6-diazepanylpyridine for 3-amino-2-azacyclooctylpyridine, the title compound was obtained.

Melting point: at 220 ℃.

Example 6

8- (1-Azepanyl) -2- (dipropylamino) -6- (4-morpholinyl) pyrido [3, 4-d ] pyrimidin-4 (3H) -one

Following the procedure as in example 1, but substituting 3-amino-2-azepanyl-6- (4-morpholinyl) pyridine for 3-amino-2-azacyclooctylpyridine, the title compound was obtained.

Melting point: at 250 ℃ to obtain a mixture.

Example 7

8- (1-azepanyl) -2, 6-bis (4-morpholinyl) pyrido [3, 4-d ] pyrimidin-4 (3H) -one

The title compound was obtained by the procedure as in example 6, but substituting morpholine for di-n-propylamine.

Melting point: at 240 ℃.

Example 8

2-amino-8- [ (3 α, 5 β) -3, 5-dimethylmorpholinyl ] pyrido [3, 4-d ] pyrimidin-4 (3H) -one

Step A: N-ethoxycarbonyl-N' -2- (3, 5-dimethylmorpholin-4-yl) pyridylthiourea

A mixture of 0.02mol of cis/trans-3-amino-2- [4- (3, 5-dimethyl) morpholinyl ] pyridine (3.80g) and 2.62g (0.02mol) of ethoxycarbonyl isothiocyanate was stirred in 100ml of DMF at room temperature for 3 hours. The resulting mixture was poured into 200ml of water. The precipitate formed is filtered off with suction and washed with petroleum ether. The cis-or trans-isomer is separated by column chromatography (eluent: diethyl ether/cyclohexane 55/45).

And B: 2-amino-8- [ (3 α, 5 β) -3, 5-dimethylmorpholinyl ] pyrido [3, 4-d ] pyrimidin-4 (3H) -one

0.002mol of the cis-thiourea from step A was dissolved in 100ml of DMF and the solution thus formed was cooled to 0 ℃ and then saturated with gaseous ammonia. 0.002mol (0.50g) of mercuric chloride was added. At the end of 15 minutes the ice bath was removed and the mixture was stirred at room temperature for 3 hours. After addition of 150ml of ethyl acetate, the solution is filtered through kieselguhr (Celite) and the solvent is distilled off under reduced pressure. The precipitate thus obtained was again dissolved in 50ml of DMF and heated under reflux for 2 hours. After hot filtration, DMF was evaporated under reduced pressure. The solid thus obtained is charged with a minimum amount of acetonitrile, filtered off with suction through a glass filter and then recrystallized from acetonitrile.

Melting point: above 260 ℃.

Example 9

2-amino-8- [ (3 α, 5 α) -3, 5-dimethylmorpholinyl ] pyrido [3, 4-d ] pyrimidin-4 (3H) -one

Using trans-N-ethoxycarbonyl-N' -2- [3- (3, 5-dimethyl) morpholin-4-yl ] pyridinyl-thiourea obtained in example 8 step a and following the procedure as in example 8 step B, the title compound is obtained.

Example 10

8- [ (3 α, 5 α) -3, 5-dimethylmorpholinyl ] -2- (dipropylamino) pyrido [3, 4-d ] pyrimidin-4 (3H) -one

The title compound was obtained following the procedure as in example 8, step B, but replacing gaseous ammonia with 0.002mol of di-n-propylamine.

Melting point: 195 ℃.

Example 11:

8- [ (3 α, 5 β) -3, 5-dimethylmorpholinyl ] -2- (dipropylamino) pyrido [3, 4-d ] pyrimidin-4 (3H) -one

The title compound was obtained by the procedure as in example 9, substituting 0.002mol of di-n-propylamine for gaseous ammonia.

Melting point: 173 ℃.

Example 12:

8- [ (3 α, 5 α) -3, 5-dimethylmorpholinyl ] -2- (4-morpholinyl) pyrido [3, 4-d ] pyrimidin-4 (3H) -one

The title compound was obtained following the procedure of example 8, step B, but replacing gaseous ammonia with 0.002mol morpholine.

Melting point: 275 ℃.

Example 13:

2-amino-8- (1-azepanyl) -6- (4-morpholinyl) pyrido [3, 4-d ] pyrimidin-4 (3H) -one

The title compound was obtained by the procedure as in example 6, but substituting gaseous ammonia for di-n-propylamine.

Sublimating at 260 ℃.

Example 14:

8-chloro-2- (dipropylamino) pyrido [3, 4-d ] pyrimidin-4 (3H) -one

Following the procedure as in example 1, but substituting 3-amino-2-chloropyridine for 3-amino-2-azacyclooctylpyridine, the title compound was obtained.

Melting point: 180 ℃ is carried out.

Example 15:

2- (dipropylamino) -8- (1-pyrrolidinyl) pyrido [3, 4-d ] pyrimidin-4 (3H) -one

The title compound was obtained by following the procedure as in example 1, substituting 3-amino-2- (1-pyrrolidinyl) pyridine for 3-amino-2-azacyclooctylpyridine.

Melting point: at 220 ℃.

Example 16

8- (3, 4-Dimethoxyphenyl) -2- (dipropylamino) pyrido [3, 4-d ] pyrimidin-4 (3H) -one

The title compound was obtained by the procedure as in example 1, substituting 3-amino-2- (3, 4-dimethoxyphenyl) pyridine for 3-amino-2-azacyclooctylpyridine.

Melting point: 202 ℃.

Pharmacological study

Example A:kinase panel screening

The products of the invention show valuable properties using commercially available kinases using conventional screening methods:

● the activating properties of several products of the invention on certain kinases;

● inhibitory properties of several products of the invention against other kinases;

● other products have potentiated properties for kinase agonists or inhibitors.

Example B:blood lipid reducing activity

The products of the invention were tested in vivo in obese ob/ob mice, which were used as obesity-related insulin resistance models. For example, oral administration of 125mg/kg of the compound of example 6 significantly reduced triglycerides, however, oral administration of 250mg/kg of metformin resulted in the same degree of reduction.

In this model, the compounds of the invention have been shown to be potent hypolipidemic agents.

Example C:acute toxicity study

Acute toxicity was assessed following oral administration of increasing doses of test compound to groups of mice each comprising 8 mice (26 ± 6 g). Animals were observed throughout the first day at regular intervals and daily for two weeks after treatment.

The compounds of the present invention are shown to be completely non-toxic.

Example D:pharmaceutical composition

Preparation of 1000 tablets each containing 5mg of active ingredient

Example 8 Compound 5g

Hydroxypropyl cellulose 2g

Wheat starch 10g

Lactose 100g

Magnesium stearate 3g

Talcum powder 3g

Claims

1. Compounds of formula (I'), their enantiomers, diastereomers, tautomers and addition salts thereof with a pharmaceutically acceptable acid or base,

wherein:

R₄represents a hydrogen atom or a group NR "₁R”₂Wherein R "₁And R "₂Identical or different, represent a hydrogen atom or an alkyl group or form, together with the nitrogen atom bearing them, a heterocycle;

wherein:

-the term "aryl" denotes phenyl or naphthyl;

the term "heterocycle" denotes a monocyclic or bicyclic ring system containing from 5 to 11 carbon atoms and having the exception of the bond R₁R₂、R’₁R’₂Or R'₁R”₂The system may contain, in addition to the nitrogen atom(s), one or two further heteroatoms selected from oxygen, sulphur and nitrogen, said heterocyclic system being substituted by one, two or three alkyl groups;

the term "substituted" in relation to aryl means that the phenyl or naphthyl group is substituted by one, two or three identical or different radicals chosen from halogen atoms and alkyl, alkoxy, polyhaloalkyl and hydroxyl, polyhaloalkyl being a straight or branched carbon chain containing from 1 to 3 carbon atoms and from 1 to 7 halogen atoms.

2. Compounds of formula (Γ) according to claim 1, their enantiomers, diastereomers, tautomers and addition salts thereof with a pharmaceutically acceptable acid or base, wherein NR is₁R₂Represents NH₂Di-n-propylamino or morpholinyl.

3. Compounds of formula (Γ) according to claim 1, their enantiomers, diastereomers, tautomers and addition salts thereof with a pharmaceutically acceptable acid or base, wherein R₃Represents 3, 4-dimethoxyphenyl, 3, 5-dimethylmorpholinyl, thiomorpholinyl, aza * yl, perhydroquinolinyl or pyrrolidinyl or a chlorine atom.

4. Compounds of formula (Γ) according to claim 2, their enantiomers, diastereomers, tautomers and addition salts thereof with a pharmaceutically acceptable acid or base, wherein R₃Represents 3, 4-dimethoxyphenyl, 3, 5-dimethylmorpholinyl, thiomorpholinyl, aza * yl, perhydroquinolinyl or pyrrolidinyl or a chlorine atom.

5. The compounds of formula (Γ) according to any of claims 1 to 4, their enantiomers, diastereomers, tautomers and addition salts thereof with a pharmaceutically acceptable acid or base, wherein R is₄Represents a hydrogen atom or a morpholinyl or aza * group.

6. A compound according to claim 1, selected from:

8- (1-azacyclooctyl) -2- (dipropylamino) pyrido [3, 4-d ] pyrimidin-4 (3H) -one,

8- ((4a α, 8a α) -octahydro-1- (2H) quinolinyl) -2- (dipropylamino) pyrido [3, 4-d pyrimidin-4 (3H) -one,

8- ((4a beta, 8a alpha) -octahydro-1- (2H) quinolinyl) -2- (dipropylamino) pyrido [3, 4-d ] pyrimidin-4 (3H) -one,

6, 8-bis (1-azepanyl) -2- (dipropylamino) pyrido [3, 4-d ] pyrimidin-4 (3H) -one,

8- [ (alpha, 5 beta) -3, 5-dimethylmorpholinyl ] -2- (dipropylamino) pyrido [3, 4-d ] pyrimidin-4 (3H) -one,

8- [ (3 α, 5 α) -3, 5-dimethylmorpholine ] -2- (dipropylamino) pyrido [3, 4-d ] pyrimidin-4 (3H) -one,

8-chloro-2- (dipropylamino) pyrido [3, 4-d ] pyrimidin-4 (3H) -one,

7. Process for the preparation of compounds of formula (Γ) according to claim 1, their enantiomers, diastereomers, tautomers and addition salts thereof with a pharmaceutically acceptable acid or base, characterized in that: using a compound of formula (II) as a starting material,

wherein R is₃And R₄As defined in formula (I),

condensing a compound of formula (II) with a compound of formula (III),

S＝C＝N-C(O)OR₂₀ (III)

wherein R is₂₀Represents an alkyl group or an aryl-alkyl group,

to generate the compound shown in the formula (IV),

HNR₁R₂ (V)

wherein R is₁And R₂As defined in formula (I),

to produce a compound of formula (I), optionally

-purifying the compound of formula (I) according to conventional purification methods;

-separating the compound of formula (I) into its stereoisomers according to conventional separation techniques;

-converting the compound of formula (I) into its addition salts with a pharmaceutically acceptable acid or base.

8. A pharmaceutical composition comprising as active ingredient at least one compound according to any one of claims 1 to 6, alone or in combination with one or more pharmaceutically acceptable, inert, non-toxic excipients or carriers.

9. Use of a compound according to any one of claims 1 to 6 for the preparation of a medicament for the treatment or prevention of hyperlipidemia.