AU711057B2 - 2-azabicyclo(2,2,1)heptane derivatives, their preparation and their application - Google Patents
2-azabicyclo(2,2,1)heptane derivatives, their preparation and their application Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
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Description
WO 96/38447 1 PCT/FR96/00793 2-AZABICYCLO[2,2,1]HEPTANE DERIVATIVES, THEIR PREPARATION AND THEIR APPLICATION The present invention relates to 1R or 2S 2-azabicyclo[2.2.1]heptane derivatives of general formula: IR HO HO H or HO N-R
HO
IS N-R to their preparation and to their application.
In the general formulae and R represents a hydrogen atom radical or, respectively, a radical of general formula: R R Ior Ar rAr in which R i represents an alkyl radical containing 1 to 4 carbon atoms and Ar represents a phenyl or a- or 3naphthyl radical optionally substituted by one or more 15 identical or different atoms or radicals chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms, the alkoxy radical containing 1 to 4 carbon atoms or the nitro radical.
Preferably, Ri represents a methyl or ethyl radical and Ar represents a phenyl radical optionally 2 substituted by one or more methyl or methoxy radicals.
More particularly still, R, represents a methyl radical and Ar represents a phenyl radical.
According to the invention, the compounds of general formula or in which R respectively represents a radical of general formula (II) or (II') can be obtained by bishydroxylation of a product of general formula: 1R
R
N Ar (Hi) or R I IS N Ar in which R, and Ar are defined as above.
e** The bishydroxylation is generally carried out a by operating under the conditions described by a V. VanRheenen et al., Tetrahedron Letters, 23, 1973- 6: 1976 (1976). More particularly, the oxidation can be a 15 carried out by means of potassium permanganate or of osmium tetroxide, the reaction being carried out in the presence of N-methylmorpholine oxide or of a triethylamine oxide or of potassium ferricyanide
(K
3 FeCN 6 The reaction is generally carried out in an se**: 20 aqueous/organic medium, such as a water/tert-butanol or water/acetone mixture.
The oxidizing agent should generally be chosen so that only the 5,6-dihydroxy derivative in the exo form is formed.
L 25 The compound of general formula (III) or (III') can be obtained by a Diels-Alder reaction between a homochiral amine of general formula: R, Ri (IV) or Ar NH, (IV) or NH V) A R NH 2 in which R i and Ar are defined as above, in the form of a salt, preferably with an inorganic acid such as hydrochloric acid, formaldehyde and cyclopentadiene, the reaction being carried out under the conditions described by S.D. Larsen and P.A. Grieco, J. Amer.
Chem. Soc., 107, 1768-1769 (1985).
The implementation of the process results, from a homochiral amine of R or S form, in a mixture of 2-diastereoisomers which, reacting in the same way in the subsequent bishydroxylation stage, should not o necessarily be separated.
According to the invention, the compound of 44::o general formula or in which R represents a oo hydrogen atom can be obtained by hydrogenolysis of a compound of general formula or in which R represents a radical of general formula (II) or 20 by means of hydrogen in the presence of a catalyst such as palladium-on-charcoal, the reaction being-carried *4 out in an organic solvent such as an alcohol, for 4 example methanol.
The 1R isomer of general formula in which R represents a radical of general formula (II) can be isolated from a mixture of the compounds of general formula and by diastereoselective crystallization with an optically active organic acid in an appropriate organic solvent. It is particularly advantageous to use L-dimethoxysuccinic acid in an aliphatic alcohol such as isopropanol.
The compounds of general formula are particularly useful for preparing the compounds which form the subject of United States Patent US 5,364,862 and which are agents which are active in the treatment of cardiovascular diseases, such as hypertension and myocardial ischaemia.
[l1o,2P,3I6,4a(S*) 1] (3-Chloro-2thienyl)-1-ethylethyl]amino]-3H-imidazo[4,5-b]pyridin- 3-yl]-N-ethyl-2,3-dihydroxycyclopentanecarboxamide of formula: OH OH 0 is of very particular advantage.
The compounds of general formula are particularly useful for preparing the carbosugar of general formula: NH-j
(V)
R"-O O-R' in which R, represents a carboxyl radical, anralkoxycarbonyl radical in which the alkyl part contains 1 to 4 carbon atoms, an N-alkylaminocarbonyl radical in which the alkyl part contains 1 to 4 carbon atoms, or a hydroxymethyl or alkoxymethyl radical, and R' and R", which are identical or different, represent a hydrogen atom, an aliphatic organic acid residue containing 2 to 4 carbon atoms, such as an acetyl or propionyl radical, or an aromatic acid residue, such as a benzoyl residue, or else R' and R" together form a methylene radical, the carbon atom of which is optionally substituted by *one or more identical or different radicals chosen from i alkyl radicals containing 1 to 4 carbon atoms, which can together form an alicyclic radical containing 5 or 15 6 carbon atoms, or phenyl radicals, and Gi represents a hydrogen atom or a protecting group G 2 for the amino 44* functional group. More particularly, R 2 represents an ethylaminocarbonyl or hydroxymethyl radical and R' and 4 R" together form an isopropylidene radical.
20 The carbosugar of general formula (V) constitutes one of the components of the structure of the compounds claimed in United States Patent US 5,364,862.
The carbosugar of general formula can be prepared from the product of general formula in the following way.
The hydroxyl functional groups of the compound of general formula in which R represents a hydrogen atom or a radical of general formula (II) cair-be protected in the ester or acetal form in order to give a product of general formula: R'I-Oi R"-O N-R
(VI)
in which R represents a hydrogen atom or a radical of general formula (II) and and R" 1 which are identical or different, represent an aliphatic organic acid residue containing 2 to 4 carbon atoms, such as an acetyl or propionyl radical, or an aromatic acid residue, such as a benzoyl residue, or else R'I and R", together form a methylene radical, the carbon atom of 15 which is optionally substituted by one or more identical or different radicals chosen from alkyl radicals containing 1 to 4 carbon atoms, which can together form an alicyclic radical containing 5 or 6 a carbon atoms, or phenyl radicals.
20 The protection of the hydroxyl radicals is generally carried out under the usual esterification or acetalization conditions, for example by reacting with acetic or propionic acid in the presence of p-toluenesulphonic acid in an organic solvent such as an aromatic hydrocarbon, for example benzene or toluene, the water being separated off as it is formed, or by reacting with an aldehyde or with a ketone, optionally in the acetal form, in the presence of an acid, such as trifluoroacetic acid, in an organic solvent such as an aromatic hydrocarbon, for example benzene or toluene, at a temperature of between 50 0
C
and the reflux temperature of the reaction mixture.
The compound of general formula (VI) in which R represents a radical of general formula (II) can be converted to the product of general formula (VI) in which R represents a hydrogen atom by hydrogenolysis.
The hydrogenolysis is generally carried out by means of hydrogen, optionally under pressure, in the presence of a catalyst, such as palladium-on-charcoal, in an organic solvent such as an alcohol, for example
C
methanol, ethanol or isopropanol, at a temperature of between 0 and 50 0
C.
The product of general formula which is a novel product, constitutes another subject of the S C present' invention.
CC«
The product of general formula (VI) in which R represents a hydrogen atom can be converted to the compound of general formula: -N-L (V in which R' and R"i are defined as above and G 2 represents a protecting group for the amino functional group, by reaction with a suitable reagent which allows selective introduction of a protecting group.
The protecting groups are chosen ffom those which can subsequently be selectively removed. Mention may be made, among protecting groups which are particularly well suited, of the following radicals: chloroacetyl, methoxymethyl, 2,2,2trichloroethoxycarbonyl, t-butyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, diphenylmethyl, trialkylsilyl, allyloxycarbonyl, benzyloxycarbonyl, in which the phenyl ring is optionally substituted by a halogen atom, by an alkyl radical containing 1 to 4 carbon atoms or by an alkyloxy radical containing 1 to 4 carbon atoms, or t-butoxycarbonyl. Mention may be made, among the other protecting groups which are particularly well suited, of those which are described :*by T.W. Greene and P.G.M. Wuts, "Protecting Groups in 20 Organic Synthesis", Chapter 7, 2nd edition, John Wiley Sons (1991).
The t-butoxycarbonyl group is of very particular advantage.
.The compound of general formula (VII) in which 25 G 2 represents a t-butoxycarbonyl radical can be obtained directly from a product of general formula (VI) in which R represents a radical of general formula (II) by simultaneous hydrogenolysis and tertbutoxycarbonylation.
The reaction is generally carried out by simultaneously reacting hydrogen, in the presence of a catalyst such as palladium-on-charcoal, and di-t-butyl dicarbonate with a product of general formulA the reaction being carried out in an organic solvent such as an alcohol, for example methanol, ethanol or isopropanol, at a temperature of between 0 and 50 0
C.
The compound of general formula (VII) is novel and constitutes another aspect of the present invention.
The compound of general formula (VII) is then oxidized to the product of general formula: 9C a
S
a a
S
a.
a. a a a R".-Ov N-G,
(VI)
0 in which R'j, R" 1 and G 2 are defined as above.
The oxidation is generally carried out by means o'f ruthenium oxide (RuO 4 optionally generated in situ from a precursor such as RuO 2 or RuC13 in the presence of an oxidizing agent chosen from a periodate, such as sodium periodate, a hypochlorite, such as 20 sodium hypochlorite or hypobromite, or a bromate, such as sodium bromate, or an organic tertiary amine oxide, such as N-methylmorpholine oxide or triethylamine oxide, the reaction being carried out in water or in a homogeneous or heterogeneous aqueous/organic medium, such as a water/ethyl acetate mixture.
The oxidation can also be carried out by means of sodium hypochlorite alone (bleach) or by means of potassium permanganate or by means of sodium tungstate in the presence of an oxidizing agent, such as sodium hypochlorite, aqueous hydrogen peroxide solution or an alkyl hydroperoxide.
The compound of general formula (VIII) can also be obtained by oxidation of a compound of general formula (VI) in which R represents a hydrogen atom under the conditions described above, followed by the protection of the nitrogen atom of the lactam obtained of general formula: R'-0 R" -0 N-H I
O
*0 15 in which R' 1 and are defined as above, by a protecting group as defined above.
The compounds of general formula (VIII) as defined above are novel provided that, when and R", together form a methylene radical substituted'-at the carbon atom by two CH 3 groups, then G 2 is other than a 20 group -CONHR wherein R is CH 3
CH
2 Ph or COCH 2 Cl. These compounds constitute another aspect of the present invention.
A compound of general formula (VIII) can be converted into a compound of general formula under conditions appropriate to the nature of the R 2 S substituent which has to be introduced.
The compound of general formula in which R 2 represents a carboxyl radical can be obtained by reaction of an inorganic base, such as sodium hydroxide, with the compound of general formula (VIII), followed by replacement of the protecting grCup G 2 by a hydrogen atom and optionally of the R' and radicals by hydrogen atoms.
The compound of general formula in which R 2 represents a carboxyl radical can be obtained by replacement of the protecting group G, of the compound of general formula (VIII) by a hydrogen atom, followed by reaction with an with an inorganic base, such as sodium hydroxide, and optionally by replacement of the and
R"
1 radicals by hydrogep atoms.
The compound of general formula in which R 2 represents an alkoxycarbonyl radical in which the alkyl part contains 1 to 4 carbon atoms can be obtained by reaction of an alkali metal alkoxide with the compound of general formula (VIII), followed by replacement of 20 the protecting group G 2 by a hydrogen atom and optionally of the and radicals by hydrogen S* atoms.
The compound of general formula in which R 2 S* represents an alkoxycarbonyl radical in which the alkyl 25 part contains 1 to 4 carbon atoms can be obtained by replacement of the protecting group G 2 of the compound of general formula (VIII) by a hydrogen atom, followed by reaction with an alkali metal alkoxide and optionally by replacement of the and radicals by hydrogen atoms.
The compound of general formula in which R 2 represents an N-alkylaminocarbonyl radical in which the alkyl part contains 1 to 4 carbon atoms can b obtained by reaction of an alkylamine with the compound of general formula (VIII), followed by replacement of the protecting group G 2 by a hydrogen atom and optionally by replacement of the and R" radicals by hydrogen atoms.
The compound of general formula in which R 2 represents an N-alkylaminocarbonyl radical in which the alkyl part contains 1 to 4 carbon atoms can be obtained by replacement of the protecting group G2 of the compound of general formula (VIII) by a hydrogen atom, followed by reaction with an alkylamine and optionally by replacement of the R and radicals by hydrogen atoms.
The compound of general formula in which R 2 20 represents a hydroxymethyl radical can be obtained by S9. reaction of a reducing agent such as a borohydride, for example sodium or potassium borohydride, with the compound of general formula (VIII), followed by replacement of the protecting group G 2 by a hydrogen atom and optionally of the and R"1 radicals by hydrogen atoms The compound of general formula in which R 2 2 k represents a hydroxymethyl radical can be obtained by 13 replacement of the protecting group G 2 of the compound of general formula (VIII) by a hydrogen atom, followed by reaction with a reducing agent such as a borohydride, for example sodium or potassium borohydride, and by optional replacement of the R'i and radice-ls by hydrogen atoms.
The compound of general formula can be used under the conditions described in United States Patent US 5,364,862 to produce therapeutically active products.
The following examples illustrate the present invention.
EXAMPLE 1 A solution of 20 g of u-S-methylbenzylamine (165 mmol) in 60 cm 3 of water, the pH of which is adjusted to 6.10 by addition of 17 cm 3 of 36% (w/v) hydrochloric acid, is introduced, under an argon atmosphere, into a 250 cm 3 three-necked round-bottomed flask equipped with a reflux condenser and a stirring system. After cooling to 5 0 C, 20 cm 3 of a 37% (w/v) aqueout formaldehyde solution are added. The mixture is 9* stirred for 5 minutes at 5 0 C and then 21.8 g of e cyclopentadiene (330 mmol) are added. The mixture is stirred for 16 hours between -5 and 0°C. The aqueous phase is separated by settling and then washed with cm 3 of pentane. Neutralization is carried out to pH by addition of concentrated sodium hydroxide solution. Extraction is then carried out with 2 times cm 3 of ethyl acetate. The aqueous phase is brought to pH 11 by addition of concentrated sodium hydroxide solution and then extracted with 2 times 70 cm 3 of ethyl acetate. The organic phases are combined, then washed with 2 times 50 cm 3 of water and then dried over sodium sulphate. After filtering and concentrating to dryness under reduced pressure, 33.10 g of 2-(a-Smethylbenzyl)-2-azabicyclo[2,2,1]hept-5-ene are obtained in the form of a slightly yellow oil.
12 g of N-methylmorpholine oxide, in 32 cm 3 of water, and then, slowly, 6.3 cm 3 of a 2.5% (w/v) solution of osmium tetroxide (OsO 4 in tert-butanol are added, at a temperature in the region of 25 0 C, to a 500 cm 3 three-necked round-bottomed flask equipped with a reflux condenser and a stirring system and containing a solution of 20 g of 2-(a-S-methylbenzyl)-2azabicyclo[2,2,1]hept-5-ene (75.34 mmol) in 220 cm 3 of tert-butanol. The mixture is stirred for 2 hours at a temperature in the region of 20 0 C and then for 3 hours at 65 0 C. After evaporation of the tert-butanol under reduced pressure, the residue is taken up in 350 cm 3 of isopropanol. After concentrating to dryness under reduced pressure, 24 g of cis-5,6-dihydroxy-2-(-Smethylbenzyl)-2-azabicyclo[2,2,1]heptane are obtained in the form of an oil. By crystallization from cyclohexane, 14 g of 5R,6S-dihydroxy-2-(a-Smethylbenzyl)-2-azabicyclo[2,2,1]heptane are obtained with an isomeric purity of greater than The N.M.R. spectrum, determined in deuterated chloroform, shows the following chemical shifts 1.21 (3H, 1.38 (1H, 1.59 (1H, 2.22 (2H, m), 2.45 (1H, dd), 2.95 (1H, 3.39 (1H, 3.78 (1H, 3.90 (1H, 7.28 (5H, m).
EXAMPLE 2 31.7 g of 2,2-dimethoxypropane (304 mmol) and then, slowly, 13 g of trifluoroacetic acid (114 mmol) are added to a 500 cm 3 three-necked round-bottomed flask, equipped with a reflux condenser and a stirring system, containing a solution of 18.4 g of 5R,6Sdihydroxy-2-(a-S-methylbenzyl)-2azabicyclo[2,2,1]heptane (76 mmol) in 130 cm 3 of toluene. The mixture is heated for 4 hours 10 minutes at 65 0 C. After cooling to 30 0 C and concentrating on a rotary evaporator in order to remove the toluene, the excess 2,2-dimethoxypropane and some of the trifluoroacetic acid, the reaction mixture is taken up in dichloromethane and is then neutralized by addition of 100 cm 3 of 2N sodium hydroxide solution. After separating by settling, drying the organic phase over sodium sulphate, filtering, treating with decolouring charcoal (30 g) for 30 minutes at reflux of the dichloromethane, filtering through clarcel and concentrating to dryness under reduced pressure, 18.8 g of 5R,6S-isopropylidenedioxy-2-(a-S-methylbenzyl)-2azabicyclo[2,2,1]heptane are obtained, the structure of which is confirmed by the proton N.M.R. spectrum which, determined in deuterated chloroform, shows the following chemical shifts 1.22 (3H, 1.23 (6H, 1.31 (1H, 1.57 (1H, 2.08 (1H, 2.34 (1H, broad 2.45 (1H, dd), 3.06 (1H, 3.40 (1H, q), 4.09 (1H, 4.19 (1H, 7.26 (5H, m).
g of 5% by weight palladium-on-charcoal, g of 5R,6S-isopropylidenedioxy-2-(a-S-methylbenzyl)- 2 -azabicyclo[2,2,1]heptane, 3.98 g of ditert-butyl dicarbonate and 36 cm 3 of methanol are introduced into a 250 cm 3 three-necked round-bottomed flask equipped with a stirring system. The apparatus is purged with argon and then with hydrogen and is then placed under a hydrogen atmosphere at 25 0 C. The reaction is continued for 5 hours, a purge with hydrogen being carried out every quarter of an hour in order to remove the carbon dioxide gas formed.
After filtering through clarcel and concentrating to dryness under reduced pressure, 4.84 g of 5R,6S-isopropylidenedioxy-2-(tert-butoxycarbonyl)-2azabicyclo[2,2,1]heptane are obtained, the structure of which is confirmed by the N.M.R. spectrum which, determined in d6-dimethyl sulphoxide, shows the following chemical shifts 1.16 3H), 1.28 (s, 3H), 1.32 1H), 1.34 3H), 1.65 1H), 2.38 (m, 1H), 2.65 1H), 2.99 1H), 3.84 1H), 3.94 (d, 1H), 4.16 1H).
270 mg of 5R,6S-isopropylidenedioxy-2-(tertbutoxycarbonyl)-2-azabicyclo[2,2,1]heptane (1 mmol) and mg of RuO 2
-H
2 0 (0.3 equivalent) are introduced into a cm 3 tube. 10 cm 3 of ethyl acetate and 720 mg of water equivalents) are added. 2.14 g of sodium periodate equivalents) are then added and the tube is hermetically sealed. The tube is agitated for 16 hours at 50 0 C. The reaction mixture is filtered through clarcel and then extraction is carried out with 2 times cm 3 of ethyl acetate. The organic phases are dried over sodium sulphate. After filtering and concentrating to dryness under reduced pressure, 245 mg of a solid are obtained, which solid contains 68% of 5R,6Sisopropylidenedioxy-2-(tert-butoxycarbonyl)-2azabicyclo[2,2,1]heptane-3-one and 32% of starting material. The structure of the product obtained is confirmed by the N.M.R. spectrum which, determined in d6 dimethyl sulphoxide, shows the following chemical shifts 1.38 (9H, 1.23 (3H, 1.33 (3H, s), 1.85 (1H, 1.93 (1H, 2.69 (1H, 4.24 (1H, s), 4.41 (1H, 4.51 (1H, d).
EXAMPLE 3 1.47 g of 5R,6S-isopropylidenedioxy-2- (tert-butoxycarbonyl)-2-azabicyclo[2,2,1]heptane-3-one, in solution in 10 cm 3 of anhydrous toluene, and then approximately 0.7 cm 3 of ethylamine are introduced into a 25 cm 3 autoclave equipped with magnetic stirring. The autoclave is closed and is heated at a temperature of between 90 and 100 0 C for 21 hours. After cooling, the toluene is evaporated and the residue is taken up in cm 3 of dichloromethane and 10 cm 3 of water. After separating by settling, the organic phase is washed with 10 cm 3 of water. The combined aqueous layers are washed with 10 cm 3 of dichloromethane. The combined organic phases are washed with 10 cm 3 of a saturated sodium chloride solution and then dried over sodium sulphate. After filtering and concentrating to dryness under reduced pressure, 1.58 g of a product are obtained, which product contains 95% of 2R,3Sisopropylidenedioxy-4-R-tert-butoxycarbonylamino-1-Sethylaminocarbonylcyclopentane, the structure of which is confirmed by the N.M.R. spectrum which, determined in d6 dimethyl sulphoxide, shows the following chemical shifts: 0.95 3H), 1.14 3H), 1.31 12H), 1.55 1H), 2.11 1H), 2.64 1H), 3.00 (qi, 2H), 3.77 1H), 4.23 1H), 4.54 1H), 7.07 1H), 8.12 1H).
1.22 g of 2R,3S-isopropylidenedioxy-4Rtert-butoxycarbonylamino-lSethylaminocarbonylcyclopentane and 10 cm 3 of dichloromethane are introduced into a 25 cm 3 roundbottomed flask. 0.85 g of trifluoroacetic acid is added, with magnetic stirring, at a temperature in the region of 25 0 C. After stirring for 6 hours and concentrating to dryness, 1.16 g of 2R,3Sisopropylidenedioxy-4R-amino-lSethylaminocarbonylcyclopentane trifluoroacetate are obtained, the structure of which is confirmed by the N.M.R. spectrum which, determined in d6 dimethyl sulphoxide, shows the following chemical shifts: 0.79 3H), 1.03 3H), 1.19 3H), 1.42 1H), 2.05 1H), 2.52 1H), 2.89 (qi, 2H), 3.04 1H), 4.16 1H).
EXAMPLE 4 A solution of 0.5 mmol of a mixture (78/22 in moles) of 5R,6S-dihydroxy-2-(a-S-methylbenzyl)-2azabicyclo[2,2,1]heptane and of 5S,6R-dihydroxy-2- methylbenzyl)-2-azabicyclo[2,2,1]heptane and of mmol of L-dimethoxysuccinic acid in 1 cm 3 of isopropanol is stirred for 24 hours at a temperature varying from 25 0 C at the start to 5 0 C. The crystals obtained are separated by filtration and dried. 110 mg of 5R,6S-dihydroxy-2-(a-S-methylbenzyl)-2azabicyclo[2,2,1]heptane are thus obtained with an enantiomeric excess of 97%.
The mixture (78/22 in moles) of 5R,6Sdihydroxy-2-(a-S-methylbenzyl)-2azabicyclo[2,2,1]heptane and of 5S,6R-dihydroxy-2-(a-Smethylbenzyl)-2-azabicyclo[2,2,1]heptane can be obtained in the following way: 4.12 g of N-methylmorpholine oxide in 11 cm' of water, and then, slowly, 360 gl of a 2.5% (w/v) solution of osmium tetroxide (OsO 4 in tert-butanol are added, at a temperature in the region of 25°C, to a 250 cm 3 three-necked round-bottomed flask, equipped with a reflux condenser and a stirring system, containing a A/7 c^'j solution of 7 g of 2-(a-S-methylbenzyl)-2azabicyclo[2,2,1]hept-5-ene (35 mmol) in 70 cm 3 of tertbutanol. The mixture is stirred for 1 hour at a temperature in the region of 20 0 C and then for 4 hours at 65 0 C. After evaporating the tert-butanol under reduced pressure, the residue is taken up in 150 cm 3 of isopropanol. After concentrating to dryness under reduced pressure, 8.27 g of of a product are obtained, the proton N.M.R. spectrum of which shows that it is composed of a mixture (78/22 in moles) of 5R,6Sdihydroxy-2-(a-S-methylbenzyl)-2azabicyclo[2,2,1]heptane and of 5S,6R-dihydroxy-2-(a-Smethylbenzyl)-2-azabicyclo[2,2,1]heptane.
EXAMPLE 568 mg of 5R,6S-isopropylidenedioxy-2-(tertbutoxycarbonyl)-2-azabicyclo[2,2,1]heptane-3-one and cm 3 of a 70% (by weight) aqueous ethylamine solution are introduced into a "Berghoff" tube. The tube is heated for 4 hours at 60 0 C with agitation. After cooling, the excess triethylamine and the water are removed under reduced pressure. After drying under reduced pressure, 650 mg of 2R,3S-isopropylidenedioxy- 4-R-tert-butoxycarbonylamino-l-Sethylaminocarbonylcyclopentane are thus obtained with a yield of 98%, the structure of which is confirmed by the proton N.M.R. spectrum and the optical rotation of which is [o]i0 15.0 (c 1, methanol).
275 Al of trifluoroacetic acid are added to a solution of 200 mg of 2R,3S-isopropylidenedioxy-4-Rtert-butoxycarbonylamino-1-Sethylaminocarbonylcyclopentane in 1.6 cm 3 of anhydrous dichloromethane. The mixture is stirred overnight at a temperature in the region of -50C. The reaction mixture is poured into 4 cm 3 of 2.5N aqueous sodium hydroxide solution. The organic layer is concentrated under reduced pressure at a temperature of less than 250C.
125 mg of a product are thus obtained, which product is dissolved in 0.5 cm 3 of tetrahydrofuran. 70 mg of benzoic acid are added to this solution. After cooling the solution obtained to a temperature in the region of 0°C, the crystals obtained are separated by filtration and washed with pentane. 138 mg of 2R,3Sisopropylidenedioxy-4R-amino-iSethylaminocarbonylcyclopentane benzoate are thus obtained.
EXAMPLE 6 pl of trifluoroacetic acid are added to a solution of 167 mg of 5R,6S-isopropylidenedioxy-2- (tert-butoxycarbonyl)-2-azabicyclo[2,2,1]heptane-3-one in 1 cm 3 of dichloromethane cooled to 0°C. The temperature is allowed to return to 23 0 C over minutes and then the mixture is stirred for 22 hours at this temperature. 90 /l of trifluoroacetic acid are again added and then the mixture is stirred for a further 1 hour at a temperature of 23°C. After evaporating under reduced pressure, 123 mg of 5R,6Sisopropylidenedioxy-2-azabicyclo[2,2,1]heptane-3-one are obtained, the purity of which, determined by high performance liquid chromatography, is in the region of 92% and the structure of which is confirmed by the proton N.M.R. spectrum.
A solution of 10 g of 5R,6Sisopropylidenedioxy-2-azabicyclo[2,2,1]heptane-3-one in 100 cm 3 of a 70% (by weight) aqueous triethylamine solution is heated at 110 0 C for 20 hours under autogenous pressure. After cooling, the excess triethylamine is removed under reduced pressure and then washing is carried out with dichloromethane in order to remove the unreacted starting material. The aqueous layer is then concentrated and dried. 10.54 g of 2R, 3 aminocarbonylcyclopentane are thus obtained.
Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
Claims (23)
1. 1R or 1S 2-azabicyclo[2.2.1]heptane derivatives of general formulae: HO JJ HO HO N-R HO IS N-R in which R is a hydrogen atom or a radical of formula: R, R1 y or Ar (II) 0Ar in which R, represents an alkyl radical containing 1 to 4 carbon atoms and Ar represents a phenyl or a- or 3- naphthyl radical optionally substituted by one or more identical or different atoms or radicals chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms, the alkoxy radical containing 1 to 4 carbon atoms o. or the nitro radical.
2. 2-azabicyclo[2.2.1]heptane derivatives ft according to claim 1 for which R, represents a methyl or ethyl radical and Ar represents a phenyl radical optionally substituted by one or more methyl or methoxy radicals.
3. 2-azabicyclo[2.2.1]heptane derivatives according to claim 1 for which RI represents a methyl radical and Ar represents a phenyl radical.
4. Process for the preparation of a compound as defined in any one of claims 1 to 3 in which R is a radical of formula (II) or which process comprises ff submitting to bishydroxylation a compound of formula: IR RI N Ar (III) or (IM) in which R, and Ar are defined as in one of claims 1, 2 or 3. Process according to claim 4, wherein the bishydroxylation is carried out by treatment with potassium permanganate or osmium tetroxide in the presence of N-methylmorpholine oxide, triethylamine oxide or potassium ferricyanide (K 3 FeCN 6
6. Process for the preparation of a compound as defined in claim 1 in which R is hydrogen, which process comprises treating a compound as defined in claim 1 in which R is a radical of formula (II) or with hydrogen in the presence of a catalyst on a support, the reacting being carried out in an organic solvent chosen from aliphatic alcohols containing 1 to 3 carbon atoms.
7. Process according to claim 6, wherein the catalyst is palladium.
8. Process for the preparation of a compound as defined in claim 1 in which R is a radical of general formula which process comprises submitting to 25 diastereoselective crystallization a mixture of compounds of formulae and as defined in claim 1, in which, respectively, R is a radical of formula (II) or the said crystallization being carried out with an optically active acid in an organic solvent choren from aliphatic alcohols containing 1 to 3 carbon atoms.
9. Process according to claim 8, wherein the optically active acid is L-dimethoxysuccinic acid. Process for the preparation of a compound of general formula: R"N-G (Vl) 0 in which R'i and R"i, which are identical or different, represent an aliphatic organic acid residue containing 2 to 4 carbon atoms, or an aromatic acid residue, or else and R"i together form a methylene radical, the carbon atom of which is optionally substituted by one or more identical or different radicals chosen from alkyl radicals containing 1 to 4 carbon atoms, which can together form an alicyclic radical containing 5 or 6 carbon atoms, or phenyl radicals, and G 2 represents a protecting group for an amino radical, which process comprises: a) protecting the hydroxyl functional groups of a compound as defined in any one of claims 1, 2 and 3 under the usual conditions for esterification or acetalization, thereby obtaining a product of general formula: *0 R" -I N-R (VI) in which and are defined as above and R is defined as in one of claims 1, 2 and 3, Sb) converting the compound of formula (VI) thus obtained into a compound of formula: R'- R" N-G (VII) R* i in which and R"i are defined above and G 2 represents a protecting group for the nitrogen atom, by either i) submitting a compound of formula (VI) as defined above in which R is a radical of general formula (II) to hydrogenolysis and to protection by treatment with a reagent which allows a protecting group f-or the nitrogen atom to be introduced, the said hydrog@nolysis and protection steps being carried out separately or simultaneously, or ii) protecting a compound of general formula (VI) in which R is a hydrogen atom by treatment with a reagent which allows a protecting group for the nitrogen atom to be introduced; and c) oxidising the compound of formula (VII) to a compound of formula (VIII).
11. Process according to claim 10 wherein, in formula VIII, and R"i, which are identical or different, are acetyl, propionyl or benzoyl groups.
12. Process according to claim 10 wherein, step a) is carried out by treatment of the compound as defined in any one of claims 1, 2 and 3 with an aliphatic acid containing 2 to 4 carbon atoms, or with an aldehyde or ketone, optionally in acetal form, in the presence of an acid in an inert organic solvent at a temperature 25 between 50 0 C and the reflux temperature of the reaction mixture. .9* 9* 9 a a a a a a a a a 9e a. a. a a a 9 a. a a 9ta*
13. Process according to claim 10, wherein in- step the hydrogenolysis is carried out by treatment with hydrogen in the presence of a catalyst and-the protection of the nitrogen atom is carried out under the usual conditions for protection, depending on the nature of the protecting group.
14. Process according to claim 10, wherein, when G 2 in formula (VII) is a tert-butoxycarbonyl radical, the hydrogenolysis and protection of step b)i) are carried out by treating a compound of formula (VI) as defined in claim 9 simultaneously with hydrogen in the presence of a catalyst and with di-tert-butyl dicarbonate in an aliphatic alcohol containing 1 to 3 carbon atoms at a temperature of between 0 and Process according to claim 13 or 14, wherein the catalyst is palladium on charcoal.
16. Process according to claim 10, wherein step c) is carried out by treating the compound of formula (VII) with ruthenium oxide (RuO 4 optionally generated in situ in the presence of an oxidizing agent.
17. Process for the preparation of a compound of formula: (VIII) a a. a a. a. a a in which R' 1 and R"i and G 2 are defined as in claim which process comprises oxidising a compound of formula: (VI) in which and are defined as in claim 10 and R is hydrogen, thereby producing a lactam, and then protecting the nitrogen atom of the lactam under the usual conditions for protection, depending on the nature of the protecting group. r'
18. A compound of general formula: (VIIi) in which and R"i, which are identical or different, represent an aliphatic organic acid residue containing 2 to 4 carbon atoms, or an aromatic acid residue, or else R'I and together form a methylene radical, the carbon atom of which is optionally substituted by one or more identical or different radicals chosen from alkyl radicals containing 1 to 4 carbon atoms, which can together form an alicyclic radical containing 5 or 6 carbon atoms, or phenyl radicals, and G 2 represents a protecting group for an amino radical; provided that, when R'i and together form a methylene radical substituted at the carbon atom by two CH 3 groups then G 2 is other than a group -CONHR wherein R is CH 3 CH 2 Ph or COCH 2 Cl.
19. A compound of general formula 0 0 0 a a a a a a a a *aa. a a a a *0 a a a. *a a a 25 (VI) in which R represents a hydrogen atom or a radical of general formula (II) as defined in one of claims 1, 2 or 3 and R' 1 and R"i, which are identical or different, represent an aliphatic organic acid residue containing 2 to 4 carbon atoms, or an aromatic acid residue, or else R'I and together form a methylene radical, the carbon 4, atom of which is optionally substituted by one or more identical or different radicals chosen from alkyl radicals containing 1 to 4 carbon atoms, which can together form an alicyclic radical containing 5 or 6 carbon atoms, or phenyl radicals.
20. A compound of general formula: N-G2 (VII) in which and which are identical or different, represent an aliphatic organic acid residue containing 2 to 4 carbon atoms, or an aromatic acid residue, or else and together form a methylene radical, the carbon atom of which is optionally substituted by one or more identical or different radicals chosen from alkyl radicals containing 1 to 4 carbon atoms, which can together form an alicyclic radical containing 5 or 6 carbon atoms, or phenyl radicals, and G 2 represents a protecting group for the amino functional group.
21. A compound as defined in any one of claims *.ii 18 to 20 wherein and R"i, which are the same or different, are acetyl, propionyl or benzoyl groups.
22. Process for the preparation of a compound of general formula: (V) 30 R"-O O-R' in which R 2 represents a carboxyl radical, an alkoxycarbonyl radical in which the alkyl part contains 1 to 4 carbon atoms, an N-alkylaminocarbonyl radical in which the alkyl part contains 1 to 4 carbon atoms, or a hydroxymethyl or alkoxymethyl radical, and R' and R", which are identical or different, represent a hydrogen atom or an aliphatic organic acid residue containing 2 to 4 carbon atoms, or an aromatic acid residue, or else R' 1 and R"i together form a methylene radical, the carbon atom of which is optionally substituted by one e-r more identical or different radicals chosen from alkyl radicals containing 1 to 4 carbon atoms, which can together form an alicyclic radical containing 5 or 6 carbon atoms, or phenyl radicals, and GI represents a hydrogen atom or a protecting group G 2 for the amino functional group, characterized in that, depending on the nature of the R 2 radical which it is desired to obtain, an inorganic base, an alkali metal alkoxide, an alkylamine or an alkali metal borohydride is reacted with a product of general formula: (VIII) *0 in which and R" and G 2 are defined as above, provided that, when and together form a methylene radical 25 substituted at the carbon atom by two CH 3 groups then G 2 is other than a group -CONHR wherein R is CH 3 CH 2 Ph or COCH 2 Cl; and then optionally the and radicals and- ".the protecting group G 2 are replaced by hydrogen atoms.
23. Process for the preparation of a"-compound of general formula: 5* S a S S R ONH-G, O-R' 31 in which R 2 represents a carboxyl radical, an alkoxycarbonyl radical in which the alkyl part contains 1 to 4 carbon atoms, an N-alkylaminocarbonyl radical in which the alkyl part contains 1 to 4 carbon atoms, or a hydroxymethyl or alkoxymethyl radical, and and R" 1 which are identical or different, represent a hydrogen atom or an aliphatic organic acid residue containing 2 to 4 carbon atoms, or an aromatic acid residue, or else R', and together form a methylene radical, the carbon atom of which is optionally substituted by one or more identical or different radicals chosen from alkyl radicals containing 1 to 4 carbon atoms, which can together form an alicyclic radical containing 5 or 6 carbon atoms, or phenyl radicals, and Gi represents a hydrogen atom or a protecting group G 2 for the amino functional group, characterized in that the protecting group G 2 of a product of general formula: RN-GO (VIII) -0 in which and and G 2 are defined as above, is replaced by a hydrogen atom, the product obtained is then reacted, depending on the nature of the R 2 radical which it is desired to obtain, with an inorganic base, an *alkali metal alkoxide, an alkylamine or an alkali metal 4* Sboroin which R 1 ide, and thR"e and Gthe are defined as above, isare optionally replaced by hydrogen atoms.
24. Process according to claim 22 or 23 wherein, in formula and R" I which are the same or different, are acetyl, propionyl or benzoyl groups. A compound as defined in any one of claims 1 to 3 and 18 to 21, substantially as hereinbefore described in the Examples.
26. A process as defined in any one of claims 4 to 17 and 22 to 24, substantially as hereinbefore described in the Examples.
27. A compound whenever obtained by a process as defined in any one of claims 4 to 17, 22 to 24 and 26. DATED this 12th day of August 1999 RHONE-POULENC RORER S.A. by DAVIES COLLISON CAVE Patent Attorneys for the Applicant 9 I **f *1* *S S S S S St **e S S S SB ftftft* o«oo
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR95/06353 | 1995-05-30 | ||
| FR9506353A FR2734822B1 (en) | 1995-05-30 | 1995-05-30 | NEW 2-AZABICYCLO (2.2.1) HEPTANE DERIVATIVES, THEIR PREPARATION AND THEIR APPLICATION |
| PCT/FR1996/000793 WO1996038447A1 (en) | 1995-05-30 | 1996-05-28 | 2-azabicyclo[2.2.1]heptane derivatives, preparation and application thereof |
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| AU6008796A AU6008796A (en) | 1996-12-18 |
| AU711057B2 true AU711057B2 (en) | 1999-10-07 |
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| US4954504A (en) * | 1986-11-14 | 1990-09-04 | Ciba-Geigy Corporation | N9 -cyclopentyl-substituted adenine derivatives having adenosine-2 receptor stimulating activity |
| US5063233A (en) * | 1986-11-14 | 1991-11-05 | Ciba-Geigy Corporation | N9 -cyclopentyl-substituted adenine derivatives useful as adenosine receptor agonists |
| US4803272A (en) * | 1987-02-24 | 1989-02-07 | E. I. Du Pont De Nemours And Company | S-modified adenosyl-1,8-diamino-3-thiooctane derivatives |
| US5561134A (en) * | 1990-09-25 | 1996-10-01 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Compounds having antihypertensive, cardioprotective, anti-ischemic and antilipolytic properties |
| GB9301000D0 (en) * | 1993-01-20 | 1993-03-10 | Glaxo Group Ltd | Chemical compounds |
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Non-Patent Citations (2)
| Title |
|---|
| CHEM. PHARM. BULL. 1991, 39 (5), 1112-1122 * |
| TETRAHEDRON LETT. 1989, 30 (13), 1645-1648 * |
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