CZ20003956A3 - The novel octahydro-6,10-dioxo-6H-pyridazino [1,2-a] [1,2] diazepine-1-carboxylic acid derivatives, a process for their preparation and their use in the preparation of therapeutically active compounds. - Google Patents

Abstract

Compounds of general formula (I) in the SR configuration or in the form of a mixture of RS+SS configurations, where R represents a hydrogen atom, an alkyl or aralkyl group containing up to 18 carbon atoms, where the amino function is free or protected. Use of these compounds in the preparation of therapeutically active compounds

Description

Technical field

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

SUMMARY OF THE INVENTION

The invention includes compounds of formula (I):

having the SR configuration or forming a mixture of the SR + RR configurations, wherein in the general formula R represents a hydrogen atom, an alkyl group or an aralkyl group containing up to 18 carbon atoms, wherein the amine function may be free or protected.

R is, for example, hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, or benzyl or naphthyl. When the amine functionality is protected, the protecting group is introduced by standard methods known in the art for protecting amines.

Are compounds of the general invention

A specific object of the invention of formula (IA):

O COOR

R, (IA)

having the SR configuration or forming a mixture of SR + RR configurations, wherein in the formula R is as defined above, and R 1 is either a group selected from the group consisting of

O

II

C - Ra

WITH

II

C —Rb

O O

H ¹¹

C-O-Rc or C-N Rd I x

wherein Ra, Rb, Rc and Rd are alkyl or aryl groups containing up to 18 carbon atoms, or mono- or polycyclic groups containing one or more heteroatoms,

X is hydrogen, alkyl having up to 8 carbon atoms or aryl group having up to 14 carbon atoms and R ₂ is hydrogen or Ri and _R2 together form a mono- or polycyclic radical containing one or more heteroatoms.

To protect the amines, cyclic compounds, e.g.

II o

or also

H • · · · · · · · · · · · · · · ·

Z Z b * · · · · · ·

An even more specific object of the invention are compounds of formula (ΙΑ) wherein R _T and R ₂ together form a polycyclic radical containing one or more heteroatoms, and in particular

having an SR configuration or forming a mixture of SR + SS configurations.

A specific object of the invention are compounds of formula (I) wherein R is a methyl group having the SR configuration or in the form of a mixture of the SR + SS configurations.

The invention also encompasses a preparation process characterized in that the compound of formula (II):

Haf (II) in which alk represents an alkyl group containing up to 8 carbon atoms and Hal represents a halogen atom, is treated with a compound of formula (III):

If

Aryl - CH ₉ O - C

N - H j (III)> N - H

Aryl - CH ₂ O —C

Wherein Aryl is an aryl group containing up to 14 carbon atoms to produce a compound of formula

II

which is treated with a basic agent to give a compound of formula (V):

which may optionally be treated with an alkylating agent to produce a compound of formula

Aryl -

(VI):

(VI) • · · · ···

whose treatment with a compound of formula (VII):

wherein Hal 1 represents a halogen atom and Ar represents an aryl or aralkyl group containing up to 18 carbon atoms, and R 1 and R ₂ are as defined above, a compound of formula (VIII) is prepared: *

having the SR configuration or forming a mixture of the SR + SS configurations, which are treated with a hydrogenation agent to produce a compound of formula (IX)

(IX) having an SR configuration or forming a mixture of SR + SS configurations from which the corresponding compound of formula (IA) is prepared by treatment with a condensation agent and then, if desired, liberating the amine functionality to yield a compound of formula (I) wherein the amine functionality is free.

In a preferred embodiment

- Hal and Halí mean chlorine,

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

- Aryl means a phenyl or naphthyl group,

- aralkyl means a benzyl group,

- the reaction between the compounds of formula (II) and formula (III) takes place in the presence of a base, for example in the presence of an alkali carbonate such as potassium carbonate,

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

- the alkylating agent which reacts with the compound of formula (V) is an alcohol, for example methanol,

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

- as hydrogenation agent, for example, hydrogen is used in the presence of palladium on carbon, palladium dihydroxide in the presence of talc, rhodium in the presence of alumina, ruthenium on carbon, or in the presence of Raney-nickel,

- the cyclization reaction is carried out in the presence of SOCl 2 or PCl 5, or of activated esters or in the presence of dehydrating agents such as PTSA,

- the amine is released by hydrazine.

The products (IV), (VII), (VIII) and (IX) used in the preparation are novel and are included in the invention.

An even more specific object of the invention is the products whose preparation is given below in the experimental part, in particular in the form of a racemic mixture thereof.

The present invention also provides the use of a compound of formula (I) in the form of a mixture of SS, SR or SR, characterized in that the compound is treated with a deracemizing agent of an asymmetric carbon atom in a 6-membered ring to prepare a compound of formula (balls):

COOR · 9 · 9 · 9 · 9 · 9 · 9

9 9 9 9 9

9 9 9 9 9 9 9 9 9 9 9 in the form of SS, wherein the amine function is in its free form or in a protected form, and R retains its meaning as defined above.

An even more specific object of the invention includes the above use of the compounds of formula (IA) described above for the preparation of compounds of formula (IAopt):

(IAopt) in SS form, meaning.

where R,

Ri and R ₂ retain their above and

Another even more specific object of the invention includes the above use characterized in that R represents a methyl group and the amine group is in protected form as a phthalimide group.

A further, more specific object of the invention includes the above use characterized in that a base is used as the deracemization agent, in particular a strong base such as an alkali metal or alkaline earth metal alcoholate such as sodium or potassium methylate, sodium or potassium tert.-butylate or lithiated amine such as LDA.

A very specific object of the invention includes the above-described use described below in the experimental part for the preparation of:

• ·········································

- (1S-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] diazepine-1-carboxylate.

The product of formula (I) of the SS configuration wherein R is tert-butyl and the amine is protected as a phthalimide group is described, for example, in EP 94095, and is an intermediate in the synthesis of products having therapeutic properties.

The products of formula (I) can generally be used in the synthesis of medicaments, as is clear from the aforementioned patent.

The examples below are intended to further illustrate the invention but do not limit the invention in any way.

DETAILED DESCRIPTION OF THE INVENTION

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

a) Preparation of 2,5-dibromopentanoic acid

To a mixture of 106 g of 5-bromopentanoic acid and 1 ml of phosphorus tribromide was added 39 ml of bromine. The reaction mixture is maintained at 70-80 ° C for 16 hours and 30 minutes. The reaction mixture was then brought to 100 ° C for 15 minutes and then allowed to cool to room temperature. 147 g of the expected product are obtained.

b) Preparation of ethyl 2,5-dibromopentanoate

To 50 g of the product prepared in the previous step, 15 drops of DMF and 300 ml of methylene chloride were added 24.37 g of oxalyl chloride. This mixture is kept under stirring at room temperature until the reaction is complete. The reaction mixture was cooled to 10 ° C and 50 mL of ethyl alcohol was added. The reaction mixture was then stirred at 10 ° C for 30 minutes, then allowed to warm to room temperature and stirred at room temperature for 3 hours. The mixture is then brought to dryness to give the desired product.

c) Preparation of bis (phenylmethyl) -1,2-hydrazinedicarboxylate

1.5 liters of methanol and 25 g of 80% hydrazine hydrate were placed under a nitrogen atmosphere. The reaction medium is cooled to 0 DEG C. and 75 g of benzyl chloroformate are added at this temperature, followed by a further 75 g of benzyl chloroformate together with a solution of 93 g of sodium carbonate in 1100 ml of demineralized water. The reaction mixture is kept at 0 ° C for 1 hour, then the mixture is separated and washed by displacement with a mixture of 100 ml of methanol and 100 ml of water, and then washed by displacement with 500 ml of water at 0 ° C. Drying gives 107.6 g of the desired product.

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

A suspension of 12.1 g of ethyl 2,5-dibromopentanoate and 50 cm ^{3 of} diglyme is added at 20-25 ° C to a suspension containing 10.42 g

bis (phenylmethyl) -1,2-hydrazinedicarboxylate, 65 ml diglyme and 8.26 g potassium carbonate.

The resulting suspension is heated to 90 ° C. After stirring for 48 hours, it is cooled to 20 ° C, poured into a solution containing 50 ml of 2 N hydrochloric acid and 150 ml of a mixture of water and ice, and the mixture is extracted with ethyl acetate, washed with water, dried, filtered, washed with ethyl acetate. and dried. Chromatography of the obtained product on silica (eluent: heptane 40, AcOEt 20) gave 10.71 g of the desired product.

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

A solution containing 23.25 g of the product obtained in the preceding step and 80 ml of ethanol is added to 338 ml of a 40 g / l solution of sodium hydroxide in ethanol. The reaction mixture was stirred for 5 hours and 30 minutes and then 57 mL of 2 N sodium carbonate was added. The reaction mixture was stirred again for 30 hours. 141 ml of a 2 N hydrochloric acid solution are added. Thereafter, 260 ml is distilled off from the reaction mixture at a pressure of 80-90 millibars. Extract with dichloromethane, add 20 mL of ethanol, followed by washing with water-normal sodium carbonate solution. The aqueous phases are extracted with dichloromethane. The aqueous phases were then combined, mixed and acidified with 135 ml of a 2 N hydrochloric acid solution. Extraction with dichloromethane is followed by washing with water, drying, filtration, washing with methylene chloride, concentration and drying. 146 ml of isopropyl ether are then added, followed by stirring for 1 hour at 20 ° C, filtration, washing, concentration and drying. 11.41 g of the expected product are obtained.

• • •

f) Preparation of (S) -3-methyl-1- (phenylmethyl) -tetrahydro-1,3 (2H) -pyridazinedicarboxylate and (R) -3-methyl-1- (phenylmethyl) -tetrahydro-1,3 (2H) -pyridazinedicarboxylate

220 ml of methanol and dehydrated paratoluenesulfonic acid (prepared from monohydrated PTSA and 12 ml of dichloromethane) were added to 11.05 g of the product obtained in the preceding step. The resulting suspension was stirred for 15 hours, then heated to 65 ° C and stirring was continued for 6 hours and 30 minutes.

The reaction mixture was cooled to 5 ° C, 5.5 ml of 10% sodium bicarbonate solution were added, then the mixture was concentrated under reduced pressure and the residue was taken up in a mixture of 100 ml of dichloromethane and 100 ml of water. After mixing, decantation, washing of the organic phase, extraction with dichloromethane, drying, filtration and concentration are carried out. 11.39 g of the expected product are obtained.

g) Preparation of [3S- [2 (R *), 3R *]] - 3-methyl-1- (phenylmethyl) -2- [2- (1,3-dihydro-1,3-dioxo-2H-isoindole- 2-yl) -1,5-dioxo-5- (phenylmethoxy) pentyl] tetrahydro-1,3 (2H) -pyridazine dicarboxylate and [3R- [2 (S *), 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) pyridazine dicarboxylate

A solution containing 11.01 g of the product obtained in the preceding step and 50 ml of dichloromethane is added over a period of 1 hour at about 4 ° C to a solution containing 19.88 g of phenylmethyl- (S) -gamma- (chlorocarbonyl) -1,3-dihydro- 1,3-dioxo-2H-isoindole-2-butanoate and 100 mL of dichloromethane. The reaction mixture was then stirred for 30 minutes at 4 ° C and then 4.15 ml of pyridine in 25 ml of dichloromethane was added over 1 hour and 30 minutes. In mixing • · • ·

The reaction mixture is then allowed to return slowly to room temperature, then the mixture is concentrated under reduced pressure, the residue is taken up in 200 ml of ethyl acetate, washed with saturated sodium bicarbonate solution, stirred. The mixture was washed with saturated sodium bicarbonate solution, stirred and decanted. The reaction medium is washed with a solution containing 5 ml of normal hydrochloric acid solution and 25 ml of water, then with a saturated aqueous sodium chloride solution and dried. Extraction is then carried out with ethyl acetate, followed by concentration and drying. 25.2 g of the expected product are obtained.

h) Preparation of [6S - [(IR *), 6R *]] - 1,3-dihydro-1,3-dioxo-gamma - [[6- (methoxycarbonyl) -tetrahydro-1 (2H) -pyridazinyl] carbonyl] -2H -isoindole-2-butanoic acid and [6R - [(1S *), 6R *]] -1,3-dihydro-1,3-dioxo-gamma - [[6- (methoxycarbonyl) -tetrahydro-1 (2H)] -pyridazinyl] carbonyl] -2H-isoindole-2-butanoic acid

The hydrogenation apparatus was charged with 20.23 g of the product prepared in the previous step, 250 ml of THF and 3.03 g of 10% palladium on carbon. Hydrogen was introduced for 3 hours and an additional 3.03 g of catalyst was added. The hydrogenation was continued for 22 hours, then the reaction mixture was filtered, washed with THF and evaporated. Then isopropanol (25 ml) was added, concentrated to remove THF, and isopropanol (15 ml) was added. This gives a suspension to which is added 100 ml of isopropyl ether, stirred under a nitrogen atmosphere for 2 hours, and is separated by washing with isopropyl ether with 5% isopropanol. 9.5 g of the expected product are obtained by separation and drying.

i) Preparation of (1S-cis) -methyl-9- (1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) octahydro-β, 10-dioxo-6H-pyridazino [1,2- a] [1,2] diazepine-1-carboxylate and (IR-trans) -methyl-9- (1,3-dihydro

· · ·

-1,3-dioxo-2H-isoindol-2-yl) octahydro-6,10-dioxo-6H-pyridazino- [1,2-a] [1,2] diazepine-1-carboxylate

A solution containing 1 ml of thionyl chloride and 40 ml of methylene chloride was added to the mixture containing 4.038 g of the product prepared in the preceding step, 40 ml of dichloromethane and 0.4 ml of dimethylformamide at 5 ° C. The reaction mixture was stirred for 3 hours and 30 minutes. The mixture was allowed to warm to 20 ° C, stirred for one hour and 30 minutes and concentrated. A solution containing 0.15 ml of thionyl chloride and 5 ml of methylene chloride was added to the residue. Then the reaction mixture was stirred at 20 ° C for 16 hours, cooled to about 5 ° C, and 27 mL of saturated aqueous sodium bicarbonate solution was added. Stirring is continued for 30 minutes and decanted and washed with a solution containing 10 ml of sodium bicarbonate and 40 ml of demineralized water. The mixture was stirred for 3 minutes followed by decantation, extraction of the aqueous phases with methylene chloride, drying, filtration, washing with methylene chloride and concentration under reduced pressure. 3.85 g of the expected product are obtained.

Use 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] diazepine-1-carboxylate

To a mixture containing 0.194 g of the product prepared according to Example 1, 1.5 ml of dimethylformamide and 0.75 ml of tert-butanol was added at -45 ° C / -48 ° C over 1 hour and 30 minutes a solution containing 0.029 g of tert-butyllate. potassium and 0.3 ml DMF. The resulting mixture was stirred for 1 hour and then cooled to -50 ° C and 0.4 g of dusted ammonium chloride was added. The reaction mixture was then stirred for 10 minutes at -45 ° C and 1 ml of 20% ammonium chloride was added twice in succession, after which the reaction mixture was stirred for 10 minutes. 2 ml of demineralized water are then added, followed by extraction with ethyl acetate, washing with demineralized water, decantation, concentration and drying. 0.166 g of product is obtained. and _D = -75.3 ° (1% in methanol).

Claims (15)

1. Compounds of general formula (i); (I) having the SR configuration or a mixture form of the SR + SS configurations, wherein in the above general formula R represents a hydrogen atom, an alkyl or aralkyl group containing up to 18 carbon atoms and the amine function may be free or protected. Compounds of general formula (I) according to claim 1, whose general formula is (IA): (IA) having the SR configuration or a mixture of the SR + SS configurations in which R is as defined in claim 1 and R 1 is either a group selected from the group consisting of O II C —Ra p II C —Rb • · O II or C - O - R _C O II C — N —Rd I X wherein Ra, Rb, Rc, and Rd are alkyl or 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 of up to 8 carbon atoms or an aryl group of up to 14 carbon atoms, and R ₂ represents a hydrogen atom, or R ₁ and R ₂ together form a mono- or polycyclic group containing one or more heteroatoms. Compounds of formula (IA) according to claim 1 or 2, wherein R ₁ and R ₂ together form a polycyclic group containing one or more heteroatoms and having an SR configuration or a mixture of SR + SS configurations. Compounds of formula (IA) according to claim 3, wherein:. the general formula is (1A _X ): o having an SR configuration or a mixture of SR + SS configurations. Compounds of formula (I) according to any one of claims 1 to 4, wherein R represents a methyl group. A racemic mixture of compounds of formula (I) according to claim 1 whose chemical names are as follows: (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] diazepine-1-carboxylate and (1R-trans) -methyl-9- (1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) -octahydro-β, 10-dioxo -6H-pyridazino [1,2-a] [1,2] diazepine-1-carboxylate. A process for the preparation of compounds of formula (I) according to any one of the preceding claims, characterized in that the compound of formula (II): wherein alk represents an alkyl group containing up to 8 carbon atoms and Hal represents a halogen atom, is treated with a compound of formula (III): Aryl - O-CH ² -C \ Aryl - CH ₂ O - C II (III) wherein Aryl represents an aryl group containing up to 14 carbon atoms to prepare a compound of formula (IV): O II which is treated with a basic agent to give a compound of formula (V): which may optionally be treated with an alkylating agent to prepare a compound of formula (VI): Aryl O (VI) by treatment with a compound of formula (VII) (VII) wherein Hal 1 represents a halogen atom and Ar represents an aryl or aralkyl group containing up to 18 carbon atoms, and R 1 and R ₂ as defined in claim 2, a compound of formula (VIII) is prepared: Ae (VIII) having the SR configuration or a mixture form of the SR + SS configuration, which is treated with a hydrogenation agent to produce a compound of formula (IX): having the SR configuration or a mixture of the SR + SS configurations from which the corresponding compound of formula (IA) is prepared by treatment with a condensation agent and then, if desired, liberating the amine function to give a compound of formula (I) in which amine function is free. Compounds of formulas (IV), (VIII) and (IX) according to claim 1 7 as new chemical products. • · Use of compounds of formula (I) according to any one of claims 1 to 6, in the form of mixtures of SS, SR or SR, in which a compound of formula (I) is treated with a deracemizing agent for an asymmetric ring carbon atom of 6 to form a compound of formula (lopt) in SS form: (ball) (S) COOR wherein the amine function in free or protected and R is as defined in claim 1. from claims 2 to 6 for the preparation of compounds of formula (IAopt; O in SS form: Use of compounds of formula (IA) according to any one of p < I] COOR wherein R, R 1 and R ₂ have the same meaning as in claim 2. Use according to claim 9 or 10 wherein R represents a methyl group. Use according to claim 9, 10 or 11, wherein the amine function is protected as a phthalimide group. • φ • · φ «« · · φ φφφ Use according to any one of claims 9 to 12, wherein the base is used as the deracemizing agent. Use according to claim 13, wherein the strong base is an alkali metal or alkaline earth metal alcoholate or a lithiated amine. Use according to any one of claims 10 to 14, wherein the starting component is a racemic mixture according to claim 6 and the prepared product is: (1S-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] diazepine-1-methylcarboxylate.