HK1039131B - Derivatives of octahydro-6,10-dioxo-6h-pyridazino(1,2-a)(1,2)diazepine-1-carboxylic acid, the preparation process and the use thereof - Google Patents

Description

Octahydro-6, 10-dioxo-6H-pyridazino [1, 2-a ] [1, 2] diaza * -1-carboxylic acid derivatives, preparation method and uses thereof

The invention relates to derivatives of octahydro-6, 10-dioxo-6H-pyridazino [1, 2-a ] [1, 2] diaza * -1-carboxylic acid, to processes for their preparation and to their use for the preparation of therapeutically active compounds.

US 4512924, WO 9323403, US 5723602, WO 9722619, US5,656,627 and WO 33751 describe the use of derivatives of 9-amino-octahydro-6, 10-dioxo-6H-pyridazine [1, 2-a ] [1, 2] diazepine-1-carboxylic acid as starting materials for the preparation of medicaments, the amine of which may optionally be protected in the form of a phthalimido having the 1S, 9S configuration. The diastereoisomers of SS configuration are obtained at a stage prior to cyclization by separation methods, in particular crystallization or chromatography.

The subject of the present invention is a compound of formula (I) having the SR configuration or in the form of a SR + SS mixture:

wherein R represents a hydrogen atom, an alkyl or aralkyl radical containing up to 18 carbon atoms, the amine function being in the free or protected state.

R represents, for example, H, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl, or a benzyl or naphthyl group. When amine functionality is protected, the protection can be carried out according to standard methods for protecting amines.

A particular subject of the invention is a compound having the SR configuration or in the form of a SR + SS mixture corresponding to formula (IA) below:

wherein R is as defined above, simultaneously or R₁Represents a group having the formula:

or

Ra, Rb, Rc and Rd represent alkyl, aryl groups containing up to 18 carbon atoms or mono-or polycyclic groups containing one or more heteroatoms, X represents a hydrogen atom, an alkyl group containing up to 8 carbon atoms or an aryl group containing up to 14 carbon atoms, and R₂Represents a hydrogen atom, or R₁And R₂Together form a monocyclic or polycyclic group containing one or more heteroatoms.

For example, to protect amines, cyclic compounds, for example, having the formula:

or a group having the formula:

a more particular subject of the invention is a compound of formula (IA), wherein R₁And R₂Together forming a polycyclic radical containing one or more hetero atoms, in particular corresponding to formula (1A) below₁) Compounds having the SR configuration or SR + SS mixture type:

a further particular subject of the invention is a compound of formula (I) in which R represents methyl, having the SR configuration or in the form of a SR + SS mixture.

One of the subject-matters of the invention is also a process for the preparation, which is characterized in that compounds of the formula (II) in which alk represents an alkyl radical having up to 8 carbon atoms and Hal represents a halogen atom:

with a compound of formula (III) in which Aryl represents an aromatic group containing up to 14 carbon atoms:

obtaining a compound of formula (IV):

reacting a compound of formula (IV) above with a basic reagent to obtain a compound of formula (V):

the compound of formula (V) above may optionally be reacted with an alkylating agent to obtain a compound of formula (VI):

a compound of the above formula (VI) with a compound of the following formula (VII)(wherein Hal₁Represents a halogen atom, Ar represents an aryl or arylalkyl group containing up to 18 carbon atoms, R₁And R₂Consistent with the foregoing definition):

obtaining a compound of formula (VIII) having the SR configuration or SR + SS mixture:

reacting the compound of formula (VIII) with a hydrogenating agent to obtain compounds having SR configuration or SR + SS mixture

A compound of the formula (IX):

the compound of formula (IX) above is reacted with a condensing agent to obtain the corresponding compound of formula (IA), and then, if desired, the amine functional group is released to obtain the compound of formula (I) wherein the amine functional group is free.

In a preferred embodiment:

-Hal and Hal₁Represents a chlorine atom, and represents a chlorine atom,

-alk represents an alkyl group containing up to 4 carbon atoms,

aryl represents a phenyl or naphthyl group,

-aralkyl represents a benzyl group,

reacting a compound of formula (II) with a compound of formula (III) in the presence of a base, for example a basic carbonate such as potassium carbonate,

the alkaline agent which reacts with the compound of formula (IV) is sodium hydroxide or potassium hydroxide,

the alkylating agent which is reacted with the compound of formula (V) is an alcohol such as methanol,

the condensation reaction between the compounds of formula (VI) and (VII) is carried out in the presence of a base, such as pyridine, TEA, diisopropylamine,

-hydrogenating agents such as hydrogen in the following cases: palladium hydroxide in the presence of palladium on carbon, in the presence of talc, rhodium in the presence of alumina, ruthenium on carbon or raney nickel,

in SOCl₂、PCl₅Activated ester or cyclisation in the presence of a dehydrating agent such as PTSA,

amine release with hydrazine.

The products (IV), (VII), (VIII) and (IX) used during the process are novel products which are themselves also subject of the present invention.

A more specific subject of the invention is the products, in particular the racemic mixtures, the preparation of which is given in the experimental section below.

Also subject of the invention is said use, characterized in that a compound of formula (I), in SS, SR mixture form or SR form, is reacted with a deracemizing agent having an asymmetric carbon atom carried by the 6-membered ring, obtaining a compound of formula (Iopt) in SS form:

wherein the amine function is free or protected and the meaning of R is as defined above.

A more particular subject of the invention is the use of a compound of formula (IA) as defined above, for the preparation of the SS form of a compound of formula (IAopt) below:

r, R therein₁And R₂Keeping its previous definition unchanged.

A more particular subject of the invention is said use, characterized in that R represents a methyl group and in that the amine function is protected in the form of a phthalimido group.

A more particular subject of the invention is said use, characterized in that the deracemizing agent is a base, in particular a strong base, such as an alkali metal or alkaline earth metal alcoholate (e.g. sodium or potassium methylate, sodium or potassium tert-butylate) or lithiated amine (lithiatedamine) such as LDA.

A very specific subject of the invention is the use described in the experimental section below for the preparation of the following compounds:

- (1 s-cis) methyl-9- (1, 3-dihydro-1, 3-dioxo-2H-isoindol-2-yl) -3, 4, 7, 8, 9, 10-hexahydro-6, 10-dioxo-6H-pyridazino [1, 2-a ] [1, 2] -diaza * -1-carboxylate.

Products of formula (I) with SS configuration, in which R is a tert-butyl group, the amine being protected in the form of a phthalimido group, are described, for example, in patent EP 94095, this compound being an intermediate in the synthesis of products with therapeutic action.

The products of formula (I) can be used generally for the synthesis of the medicaments indicated in the above patents.

The following examples are intended to illustrate the invention, but are not intended to be limiting thereof.

Example 1:(1S-cis) methyl-9- (1, 3-dihydro-1, 3-dioxo-2H-isoindol-2-yl) -octahydro-6, 10-dioxo-6H-pyridazino [1, 2-a ]][1，2]-diaza * -1-carboxylate and methyl (1R-trans) -9- (1, 3-dihydro-1, 3-dioxo-2H-isoindol-2-yl) -octahydro-6, 10-dioxo-6H-pyridazino [1, 2-a ]][1，2]-twoAza * -1-carboxylic acid esters

a) Preparation of 2, 5-dibromopentanoic acid

39ml of bromine were added to a mixture of 106g of 5-bromovaleric acid and 1ml of phosphorus tribromide. The reaction mixture is heated to 70-80 ℃ for 16.5 hours. The reaction medium is then heated to 100 ℃ for 15 minutes and then allowed to cool to room temperature. 147g of the desired product are obtained.

b) Preparation of ethyl 2, 5-dibromovalerate

To a mixture containing 50g of the product prepared in the preceding stage, 15 drops of DMF and 300ml of dichloromethane were added 24.37g of oxalyl chloride. The reaction mixture was stirred at room temperature until the reaction was complete. The reaction mixture was then cooled to 10 ℃ and 50ml of ethanol were added. The reaction medium is stirred at 10 ℃ for 30 minutes, taken off to room temperature and stirred at room temperature for 3 hours. Drying to obtain the required product.

c) Preparation of bis (benzyl) 1, 2-hydrazinecarboxylate

1.5 l of methanol are placed under nitrogen with 25g of 80% hydrazine monohydrate solution. The reaction medium is cooled to 0 ℃ and 75g of benzyl chloroformate are added at 0 ℃ and 75g of benzyl chloroformate are then added as a 1100ml softened aqueous solution of 93g of sodium carbonate. The reaction mixture was left at 0 ℃ for 1 hour, then separated by displacement with a mixture of 100ml of methanol and 100ml of water, washed and then washed by displacement with 500ml of water at 0 ℃. After drying, 107.6g of the desired product are obtained.

d) Preparation of (S) 3-ethyl-1, 2-bis (phenylmethyl) -tetrahydro-1, 2, 3-pyridazine tricarboxylate and(R) 3-Ethyl-1, 2-bis (phenylmethyl) -tetrahydro-1, 2, 3-pyridazine tricarboxylate

A suspension of 12.1g of ethyl 2, 5-dibromovalerate and 50ml of diglyme is added to a suspension containing 10.42g of bis (benzyl) -1, 2-hydrazinedicarboxylate, 65ml of diglyme and 8.26g of potassium carbonate at 20-25 ℃.

The suspension obtained was heated at 90 ℃. Stirred for 48 hours and then cooled to 20 ℃ and poured into a solution containing 50ml of 2N hydrochloric acid and 150ml of ice-water mixture, extracted with ethyl acetate, washed with water, dried, filtered, washed with ethyl acetate and dried. The product obtained is chromatographed on silica (heptane 40, AcOEt 20 as eluent) to yield 10.71g of the desired product.

e) Preparation of (S)1- (phenylmethyl) -tetrahydro-1, 3(2H) -pyridazine dicarboxylate and(R)1- (phenylmethyl) -tetrahydro-1, 3(2H) -pyridazine dicarboxylate

A solution containing 23.25g of the product of the previous stage and 80ml of ethanol is added to 338ml of a 40g/l solution of sodium hydroxide in ethanol. Stirring was continued for 5.5 hours, then 57ml of 2N soda was added. The reaction mixture was stirred continuously for 30 hours. 141ml of 2N hydrochloric acid solution were added. 260ml of the reaction mixture were distilled at 80 to 90 mbar. Extraction with dichloromethane, addition of 20ml of ethanol and washing with aqueous ordinary soda (water-normal solution of soda). The aqueous phase was extracted with dichloromethane. The aqueous phases are combined, stirred and acidified with 135ml of 2N hydrochloric acid solution. Extracted with dichloromethane, then washed with water, dried, filtered, washed with dichloromethane, concentrated and dried. 146ml of isopropyl ether was added, followed by stirring at 20 ℃ for 1 hour, filtration, washing, concentration and drying. 11.41g of the desired product are obtained.

f) Preparation of (S) 3-methyl-1- (phenylmethyl) tetrahydro-1, 3(2H) -pyridazine dicarboxylate and (R) 3-methyl 1- (phenylmethyl) tetrahydro-1, 3(2H) -pyridazine-dicarboxylic acid ester

220ml of methanol and dehydrated p-toluenesulfonic acid (prepared from PTSA monohydrate and 12ml of dichloromethane) were added to 11.05g of the product prepared in the preceding stage. The suspension obtained was stirred continuously for 15 hours, then heated to 65 ℃ and stirred continuously for 6.5 hours. After cooling to 5 ℃, 5.5ml of a 10% sodium bicarbonate solution was added, then concentrated under reduced pressure and dissolved in a mixture of 100ml of dichloromethane and 100ml of water. After stirring, decantation was carried out, the organic phase was washed, extracted with dichloromethane, dried, filtered and concentrated. 11.39g of the desired product are obtained.

g) Preparation of [3S- [2 (R) ] ^* )，3R ^* ]]3-methyl-1- (phenylmethyl) 2- [2- (1, 3-dihydro-1, 3-dioxo-) 2H-isoindol-2-yl) -1, 5-dioxo-5- (phenylmethoxy) pentyl]Tetrahydro-1, 3(2H) pyridazines Dicarboxylic acid ester and [3R- [2 (S) ^* )，3R ^* ]]3-methyl-1- (phenylmethyl) 2- [2- (1, 3-dihydro-1, 3-di oxo-2H-isoindol-2-yl) -1, 5-dioxo-5- (phenylmethoxy) pentyl]Tetrahydro-1, 3(2H) Pyridazine dicarboxylic acid esters

A solution containing 11.01g of the product prepared in the preceding stage and 50ml of dichloromethane is added at 4 ℃ to a solution containing 19.88g of (S) - γ - (gamma) (chlorocarbonyl) -1, 3-dihydro-1, 3-dioxo-2H-isoindole-2-butyric acid benzyl ester and 100ml of dichloromethane in one hour. After stirring for 30 minutes at 4 ℃ a solution of 4.15ml pyridine in 25m dichloromethane was added over 1.5 hours. The reaction medium is stirred and allowed to slowly fall to room temperature, then concentrated under reduced pressure, dissolved in 200ml of ethyl acetate, washed with a saturated sodium hydrogen carbonate solution, followed by stirring for 30 minutes, decanting, washing with saturated sodium hydrogen carbonate, stirring and decanting. The reaction medium is washed with a solution containing 5ml of hydrochloric acid equivalent solution and 25ml of water, then with saturated aqueous sodium chloride solution and dried. Extracted with ethyl acetate, then concentrated and dried. 25.2g of the desired product are obtained.

h) Preparation of [6S- [1 (R) ] ^* )，6R ^* ]]-1, 3-dihydro-1, 3-dioxo-gamma- [ [6- (methoxycarbonyl) -tetrakis Hydrogen-1 (2H) -pyridazinyl radicals]Carbonyl radical]-2H-isoindole-2-butyric acid and [6R- [1 (S) ^* )，6R ^* ]]-1, 3-dihydro -1, 3-dioxo-gamma- [ [6- (methoxycarbonyl) -tetrahydro-1 (2H) -pyridazinyl]Carbonyl radical]-2H-isoindole- 2-butyric acid

20.23g of the product of the upper stage, 250ml of THF and 3.03g of 10% palladium on charcoal are introduced into a hydrogen apparatus. Hydrogen was introduced for 3 hours and 3.03g of catalyst were added. After 22 hours of continuous hydrogenation, filtration, washing with THF and evaporation. 25ml of isopropanol were added, then concentrated, THF was removed and 15ml of isopropanol were added. To the obtained suspension was added 100ml of isopropyl ether, followed by stirring under nitrogen atmosphere for 2 hours, separation, and washing with isopropyl ether containing 5% isopropyl alcohol. After isolation and drying, 9.5g of the desired product are obtained.

I) Preparation of (1S-cis) methyl-9- (1, 3-dihydro-1, 3-dioxo-2H-isoindol-2-yl) octahydro- 6, 10-dioxo-6H-pyridazino- [1, 2-a][1，2]-diaza * -1-carboxylic acid ester and (1R-trans) methyl Yl-9- (1, 3-dihydro-1, 3-dioxo-2H-isoindol-2-yl) octahydro-6, 10-dioxo-6H-pyridazine And- [1, 2-a][1，2]-diaza * -1-carboxylic acid ester

A solution containing 1ml of thionyl chloride and 40ml of dichloromethane was added to a mixture containing 4.038g of the upper stage product, 40ml of dichloromethane and 0.4ml of dimethylformamide at 5 ℃. Stir for 3.5 hours. The temperature was raised to 20 ℃ and then stirred for a further 1.5 hours and concentrated. A solution containing 0.15ml of thionyl chloride and 5ml of dichloromethane was added. The reaction mixture was stirred at about 20 ℃ for 16 hours, then cooled to about 5 ℃ and 27ml of saturated sodium bicarbonate solution was added. After stirring for 30 minutes, decantation was carried out, washing with a solution containing 10ml of sodium bicarbonate and 40ml of demineralized water. After stirring for 3 minutes, decantation was carried out, the aqueous phase was extracted with dichloromethane, dried, filtered, washed with dichloromethane and finally concentrated under reduced pressure. 3.85g of the desired product are obtained.

(1S-cis) methyl-9- (1, 3-dihydro-1, 3-dioxo-2H-isoindol-2-yl) octahydro-6, 10-di oxo-6H-pyridazino- [1, 2-a][1，2]Use of (diaza * -1-carboxylic acid esters

A solution containing 0.029g of potassium tert-butoxide and 0.3ml of DMF was added to a mixture containing 0.194g of the product from example 1, 1.5ml of dimethylformamide and 0.75ml of tert-butanol (terbutanol) at-45 deg.C/48 deg.C over a period of 1.5 hours. The mixture was stirred for 1 hour, then 0.4g of ammonium chloride powder was added after cooling to-50 ℃. Stirring at-45 deg.C for 10 min, and adding 20% of the total weight of the mixture1ml of ammonium chloride solution, with stirring for 10 minutes after each addition. An additional 2ml of demineralized water are added, extracted with ethyl acetate, washed with demineralized water, decanted, concentrated and dried. 0.166g of product was obtained. Alpha is alpha_D-75.3 ° (1% in methanol).

Claims (16)

1. A compound having the formula:

wherein R represents a hydrogen atom, an alkyl group or an aralkyl group containing up to 18 carbon atoms, the amine function may be a free or protected group.

2. A compound of formula (I) as defined in claim 1 corresponding to the following formula (IA):

it has the SR configuration or exists in the form of a SR + SS mixture, wherein R is as defined in claim 1 and R is₁Represents the group:

or

Wherein Ra, Rb, Rc and Rd represent alkyl or aryl radicals having up to 18 carbon atoms or mono-or polycyclic radicals having one or more heteroatoms, X represents a hydrogen atom, an alkyl radical having up to 8 carbon atoms or an aryl radical having up to 14 carbon atoms, R₂Represents a hydrogen atom, or R₁And R₂Together form a mono-or polycyclic group containing one or more heteroatoms.

3. A compound of formula (IA) as defined in claim 2 having the SR configuration or in the form of a SR + SS mixture, wherein R₁And R₂Together form a polycyclic group containing one or more heteroatoms.

4. As defined in claim 3, corresponding to formula (IA)₁) A compound of formula (IA):

it has the SR configuration or exists in the form of a SR + SS mixture.

5. A compound of formula (I) as defined in any one of claims 1 to 4 wherein R represents a methyl group.

6. A racemic mixture of a compound of formula (I) as defined in claim 1, named:

(1S-cis) methyl-9- (1, 3-dihydro-1, 3-dioxo-2H-isoindol-2-yl) -octahydro-6, 10-dioxo-6H-pyridazino [1, 2-a ] [1, 2] -diaza * -1-carboxylic acid ester and

(1R-trans) methyl-9- (1, 3-dihydro-1, 3-dioxo-2H-isoindol-2-yl) -octahydro-6, 10-dioxo-6H-pyridazino [1, 2-a ] [1, 2] -diaza * -1-carboxylate.

7. A process for the preparation of a compound of formula (I) as defined in any one of claims 1 to 6, characterized in that a compound of formula (II) wherein alk represents an alkyl group containing up to 8 carbon atoms and Hal represents a halogen atom:

with a compound of formula (III) in which Aryl represents an aromatic group containing up to 14 carbon atoms:

obtaining a compound of formula (IV):

reacting a compound of formula (IV) above with a basic agent to obtain a compound of formula (V) below:

reacting a compound of formula (V) above, optionally with an alkylating agent, to obtain a compound of formula (VI):

reacting a compound of formula (VI) above with a compound of formula (VII) below:

wherein Hal₁Represents a halogen atom, Ar represents an aryl or aralkyl radical having up to 18 carbon atoms, R₁And R₂In conformity with the definition in claim 2,

obtaining a compound of formula (VIII) having the SR configuration or in the form of a SR + SS mixture:

reacting a compound of formula (VIII) above with a hydrogenating agent to obtain a compound of formula (IX) having the SR configuration or a mixture of SR + SS:

the compound of formula (IX) above is reacted with a condensing agent to obtain the corresponding compound of formula (IA), then the amine function is released to obtain the compound of formula (I) wherein the amine function is free.

8. Compounds of formulae (IV), (VIII) and (IX) as defined in claim 7 as chemical products.

9. Use of a compound of formula (I) in SS, SR mixture form or SR configuration as defined in any one of claims 1 to 6, characterized in that the compound of formula (I) is reacted with a deracemizing agent comprising an asymmetric carbon atom on the 6-membered ring to obtain a compound of formula (Iopt) in SS configuration:

wherein the amine function is in the free or protected state and R is as defined in claim 1.

10. Use of a compound of formula (IA) as defined in any one of claims 2 to 6 for the preparation of a compound of formula (IAopt) in SS configuration:

r, R therein₁And R₂In conformity with the definition in claim 2.

11. Use according to claim 9 or 10, characterized in that R represents a methyl group.

12. Use according to claim 9 or 10, characterized in that the amine function is protected in the form of a phthalimido group.

13. Use according to claim 9 or 10, characterized in that the deracemizing agent is a base.

14. Use according to claim 13, characterized in that the base is a strong base.

15. Use according to claim 14, characterized in that the strong base is an alkali or alkaline earth metal alcoholate or a lithiated amine.

16. Use according to claim 9 or 10, characterized in that the starting material is a racemic mixture according to claim 6, the product being prepared as:

(1 s-cis) methyl-9- (1, 3-dihydro-1, 3-dioxo-2H-isoindol-2-yl) -3, 4, 7, 8, 9, 10-hexahydro-6, 10-dioxo-6H-pyridazino [1, 2-a ] [1, 2] -diaza * -1-carboxylate.