WO1996038447A1 - Derives du 2-azabicyclo[2.2.1]heptane, leur preparation et leur application - Google Patents
Derives du 2-azabicyclo[2.2.1]heptane, leur preparation et leur application Download PDFInfo
- Publication number
- WO1996038447A1 WO1996038447A1 PCT/FR1996/000793 FR9600793W WO9638447A1 WO 1996038447 A1 WO1996038447 A1 WO 1996038447A1 FR 9600793 W FR9600793 W FR 9600793W WO 9638447 A1 WO9638447 A1 WO 9638447A1
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- WO
- WIPO (PCT)
- Prior art keywords
- radical
- general formula
- product
- carbon atoms
- radicals
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- 0 COC(*C(C1)N2*)C1C2=O Chemical compound COC(*C(C1)N2*)C1C2=O 0.000 description 1
Classifications
-
- 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
-
- 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
Definitions
- the present invention relates to new 2-azabicyclo [2.2.1] heptane 1R or 2S derivatives of general formula:
- R represents a hydrogen atom radical or respectively a radical of general formula:
- Ri represents an alkyl radical containing 1 to 4 carbon atoms and Ar represents a phenyl or ⁇ - or ⁇ -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, alkoxy containing 1 to 4 carbon atoms or nitro.
- Rj represents a methyl or ethyl radical
- Ar represents a phenyl radical optionally substituted by one or more methyl or methoxy radicals.
- Ri represents a methyl radical and Ar represents a phenyl radical.
- the products of general formula (I) or (D in which R respectively represents a radical of general formula (II) or (II ') can be obtained by bis-hydroxylation of a product of general formula: in which Rj and Ar are defined as above.
- bis-hydroxylation is carried out by operating under the conditions described by V. VanRheenen et al., Tetrahedron Letters, 23, 1973-1976 (1976). More particularly, the oxidation can be carried out by means of potassium permanganate or of osmium tetroxide by operating in the presence of N-methyl morpholine-oxide or of triethylamine-oxide or of potassium ferricyanide (K3FeCN6). Generally, one operates in a hydro-organic medium such as a water-tert.butanol or water-acetone mixture. In general, the oxidant must be chosen in such a way that only the 5,6-dihydroxy derivative is formed in exo form.
- Rj and Ar are defined as above, in the form of a salt, preferably with a mineral acid such as hydrochloric acid, formaldehyde and cyclopentadiene, operating under the conditions described by SD Larsen and PA Grieco, J. Amer. Chem. Soc, 107, 1768-1769 (1985).
- a mineral acid such as hydrochloric acid, formaldehyde and cyclopentadiene
- the product of general formula (I) or (D in which R represents a hydrogen atom can be obtained by hydrogenolysis of a product of general formula (I) or (I ') in which R represents a radical of general formula (II) or (II 1 ) by means of hydrogen in the presence of a catalyst such as palladium on carbon by operating in an organic solvent such as an alcohol such as methanol.
- the 1R isomer of general formula (I) in which R represents a radical of general formula (II) can be isolated from a mixture of the products of general formula (I) and (F) by diastereoselective crystallization with an optically active organic acid in a suitable organic solvent. It is particularly advantageous to use L-dimethoxysuccinic acid in an aliphatic alcohol such as isopropanol.
- the new products of general formula (I) are particularly useful for preparing the products which are the subject of US Pat. No. 5,364,862 and which are active agents in the treatment of cardiovascular diseases such as hypertension and myocardial ischemia.
- R2 represents a carboxy radical, alkoxycarbonyl in which the alkyl part contains 1 to 4 carbon atoms, N-alkyllaminocarbonyl in which the alkyl part contains 1 to 4 carbon atoms or hydroxymethyl or alkoxymethyl
- R ′ and R ′′ which are identical or different , represent a hydrogen atom or a residue of aliphatic organic acid containing 2 to 4 carbon atoms, such as an acetyl or propionyl radical or of aromatic acid such as a benzoyl residue or else R 'and R "form together a methylene radical whose carbon atom is optionally substituted by one or more radicals, identical or different chosen from alkyl radicals containing 1 to 4 carbon atoms which can together form an alicyclic radical containing 5 or 6 carbon atoms, or the phenyl radicals, and G1 represents a hydrogen atom or a protective group G2 of the amino function. More particularly, R2 represents an ethylamino
- the carbosugar of general formula (V) constitutes one of the elements of the structure of the products claimed in American patent US 5,364,862.
- R represents a hydrogen atom or a radical of general formula (II) and R'i and R " ⁇ , identical or different, represent a residue of aliphatic organic acid containing 2 to 4 carbon atoms, such as an acetyl or propionyl or aromatic acid radical such as a benzoyl residue or else R′i and R ′′ ⁇ together form a methylene radical whose carbon atom is optionally substituted by one or more radicals, identical or different 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
- the protection of hydroxy radicals is carried out under the usual conditions of esterification or acetalization, for example by the action of acetic or propionic acid in the presence of p.toluene sulfonic acid in an organic solvent such as a hydrocarbon.
- aromatic like benzene or toluene by separating water as it is formed or by the action of an aldehyde or a ketone optionally in the form of acetal in the presence of an acid such as trifluoroacetic acid in an organic solvent such as an aromatic hydrocarbon such as benzene or toluene, at a temperature between 50 ° C and the reflux temperature of the reaction mixture.
- the product of general formula (NI) in which R represents a radical of general formula (II) can be transformed into product of general formula (NI) in which R represents a hydrogen atom by hydrogenolysis.
- the hydrogenolysis is carried out by means of hydrogen, optionally under pressure, in the presence of a catalyst such as palladium on carbon in an organic solvent such as an alcohol such as methanol, ethanol or isopropanol to a temperature between 0 and 50 ° C.
- R 'and R " ⁇ are defined as above and G2 represents a group protecting the amino function by the action of a suitable reagent allowing the selective introduction of a protective group.
- the protective groups are chosen from those which can be subsequently removed selectively.
- the protective groups which particularly suitable may be mentioned the chloroacetyl, methoxymethyl, 2,2,2-trichloroethoxycarbonyl, t.butyl, benzyl, p.nitrobenzyl, p.methoxybenzyl, diphenylmethyl, trialkylsilyl, allyloxycarbonyl, benzyloxycarbonyl radicals is optionally substituted by a halogen atom or by an alkyl radical containing 1 to 4 carbon atoms or alkyloxy containing 1 to 4 carbon atoms, or t.butoxycarbonyl.
- the product of general formula (VII) in which G2 represents a tbutoxycarbonyl 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 tert.butoxycarbonylation .
- the reaction is carried out by simultaneously reacting hydrogen in the presence of a catalyst such as palladium on carbon and di-t.butyl dicarbonate on a product of general formula (VI) by operating in a solvent organic such as an alcohol such as methanol, ethanol or isopropanol at a temperature between 0 and 50 ° C.
- a solvent organic such as an alcohol such as methanol, ethanol or isopropanol at a temperature between 0 and 50 ° C.
- the product of general formula (VII) is a new product which constitutes another object of the present invention.
- the oxidation is carried out by means of ruthenium oxide (RuO.4) possibly generated in situ from a precursor such as Ru ⁇ 2 or RuCl in the presence of an oxidant chosen from a periodate such as sodium periodate, a hypochlorite such as sodium hypochlorite or hypobromite or a bromate such as sodium bromate or an organic tertiary amine oxide such as N-methyl-morpholine-oxide or triethylamine-oxide by operating in water or in a homogeneous or heterogeneous hydro-organic medium such as a water-ethyl acetate mixture.
- RuO.4 ruthenium oxide
- 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 oxidant such as sodium hypochlorite, hydrogen peroxide or an alkyl hydroperoxide.
- the product of general formula (VIII) can also be obtained by oxidation of a product of general formula (VI) in which R represents a hydrogen atom under the conditions described above, followed by the protection of the atom d lactam nitrogen obtained from general formula:
- the product of general formula (V) in which R2 represents a carboxy radical can be obtained by the action of an inorganic base such as sodium hydroxide on the product of general formula (VIII), followed by the replacement of the protective group G2 by an atom d 'hydrogen and possibly radicals R'1 and R " ⁇ by hydrogen atoms.
- the product of general formula (V) in which R2 represents a carboxy radical can be obtained by replacing the protective group G2 of the product of general formula (VIII) with a hydrogen atom followed by the action of a base mineral such as sodium hydroxide, and possibly the replacement of the radicals R ' ⁇ and R "1 with hydrogen atoms.
- N-alkyllaminocarbonyl the alkyl part of which contains 1 to 4 carbon atoms, can be obtained by the action of an alkylamine on the product of general formula (VIII), followed by replacement of the protective group G2 with a hydrogen atom, and optionally by replacement radicals R'j and R " ⁇ by hydrogen atoms.
- N-alkyllaminocarbonyl in which the alkyl part contains 1 to 4 carbon atoms can be obtained by replacing the protective group G2 of the product of general formula (VIII) with a hydrogen atom, followed by the action of an alkylamine, and optionally replacing the radicals R'j and R " ⁇ with hydrogen atoms.
- R2 represents a hydroxymethyl radical
- a reducing agent such as a borohydride such as sodium or potassium borohydride
- the product of general formula (V) in which R2 represents a hydroxymethyl radical can be obtained by replacing the protective group G2 of the product of general formula (VIII) with a hydrogen atom followed by the action of a reducing agent such as 'a borohydride such as sodium or potassium borohydride, and the possible replacement of the radicals R'1 and R "j by hydrogen atoms.
- a reducing agent such as 'a borohydride such as sodium or potassium borohydride
- the product of general formula (V) can be used under the conditions described in American patent US Pat. No. 5,364,862 to obtain the therapeutically active products.
- a solution of 20 g of ⁇ -S-methylbenzylamine (165 mmol) in 60 cm3 of is introduced into a 250 cm3 three-necked flask provided with a condenser and a stirring system. water whose pH is adjusted to 6.10 by adding 17 cm3 of 36% hydrochloric acid (w / v). After cooling to 5 ° C., 20 cm 3 of a 37% (w / v) aqueous formaldehyde solution are added. The mixture is stirred for 5 minutes at 5 ° C. and then 21.8 g of cyclopentadiene (330 mmol) are added. The mixture is stirred for 16 hours between -5 and 0 ° C.
- EXAMPLE 2 In a 500 cm3 three-necked flask, equipped with a condenser and a stirring system, containing a solution of 18.4 g of 5R, 6S-dihydroxy-2- ( ⁇ -S- methylbenzyl) -2 -azabicyclo [2,2, l] heptane (76 mmol) in 130 cm3 of toluene, 31.7 g of 2,2-dimethoxypropane (304 mmol) are added and then slowly 13 g of trifluoroacetic acid (114 mmol) . It is heated for 4 hours 10 minutes at 65 ° C.
- reaction mixture After cooling to 30 ° C and concentration on a rotary evaporator to remove toluene, excess 2,2-dimethoxypropane and partially trifluoroacetic acid, the reaction mixture is taken up in dichloromethane and is then neutralized by adding 100 cm3 2N soda. After decantation, drying of the organic phase on sodium sulphate, filtration, treatment with bleaching black (30 g) for 30 minutes under reflux of dichloromethane, filtration on clarcel ert concentration to dryness under reduced pressure, 18.8 g of 5R are obtained.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
Claims
Priority Applications (18)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
APAP/P/1997/001149A AP973A (en) | 1995-05-30 | 1996-05-28 | 2-Azabicyclo {2.2.1} heptane derivatives preparation and application thereof. |
EA199700440A EA000963B1 (ru) | 1995-05-30 | 1996-05-28 | Производные 2-азабицикло[2.2.1]гептана, способ их получения и их применение |
RO97-02201A RO119414B1 (ro) | 1995-05-30 | 1996-05-28 | Derivaţi de 2-azabiciclo[2.2.1]heptan, procedee de preparare şi intermediari pentru acestea |
DE69615020T DE69615020T2 (de) | 1995-05-30 | 1996-05-28 | 2-azabicyclo[2.2.1]heptan-derivate, ihre herstellung und ihre anwendung |
AU60087/96A AU711057B2 (en) | 1995-05-30 | 1996-05-28 | 2-azabicyclo(2,2,1)heptane derivatives, their preparation and their application |
PL96323680A PL186195B1 (pl) | 1995-05-30 | 1996-05-28 | Nowe pochodne 2-azabicyklo [2.2.1] heptanu, sposób ich wytwarzania i ich zastosowanie |
SK1612-97A SK283809B6 (sk) | 1995-05-30 | 1996-05-28 | Deriváty 2-azabicyklo[2.2.1]heptánu a spôsob ich prípravy |
AT96917555T ATE205210T1 (de) | 1995-05-30 | 1996-05-28 | 2-azabicyclo(2.2.1)heptan-derivate, ihre herstellung und ihre anwendung |
UA97115616A UA64695C2 (en) | 1995-05-30 | 1996-05-28 | 2-azabicyclo[2.2.1]heptane derivatives and a method for preparing the same |
BR9608513A BR9608513A (pt) | 1995-05-30 | 1996-05-28 | Derivados do 2-azabiclo(2.2.1)heptano 1R ou 1S processo de preparação deste produto e produto |
DK96917555T DK0828740T3 (da) | 1995-05-30 | 1996-05-28 | 2-Azabicyclo[2.2.1]heptanderivater, deres fremstilling og anvendelse |
EP96917555A EP0828740B1 (fr) | 1995-05-30 | 1996-05-28 | Derives du 2-azabicyclo[2.2.1]heptane, leur preparation et leur application |
JP53624696A JP4097287B2 (ja) | 1995-05-30 | 1996-05-28 | 2−アザビシクロ[2.2.1]ヘプタン誘導体、それらの調製法およびそれらの用途 |
SI9630340T SI0828740T1 (en) | 1995-05-30 | 1996-05-28 | 2-azabicyclo(2.2.1)heptane derivatives, preparation and application thereof |
MXPA/A/1997/008995A MXPA97008995A (en) | 1995-05-30 | 1997-11-21 | New derivatives of 2-azabiciclo [2.2.1] heptano, its preparation and its application |
NO19975487A NO311431B1 (no) | 1995-05-30 | 1997-11-28 | Fremgangsmåte for fremstilling av karbosukkere |
BG102081A BG63084B1 (bg) | 1995-05-30 | 1997-11-28 | Нови производни на 2-азабицикло/2.2.1/хептан,получаване и приложение |
GR20010400676T GR3036536T3 (en) | 1995-05-30 | 2001-09-06 | 2-azabicyclo(2.2.1)heptane derivatives, preparation and application thereof |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR9506353A FR2734822B1 (fr) | 1995-05-30 | 1995-05-30 | Nouveaux derives du 2-azabicyclo(2.2.1)heptane, leur preparation et leur application |
FR95/06353 | 1995-05-30 | ||
US08/476,156 US5631383A (en) | 1995-05-30 | 1995-06-07 | Derivatives of 2-azabicyclo[2.2.1]heptane, their preparation and their application |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1996038447A1 true WO1996038447A1 (fr) | 1996-12-05 |
Family
ID=26231994
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/FR1996/000793 WO1996038447A1 (fr) | 1995-05-30 | 1996-05-28 | Derives du 2-azabicyclo[2.2.1]heptane, leur preparation et leur application |
Country Status (3)
Country | Link |
---|---|
US (1) | US5631383A (fr) |
FR (1) | FR2734822B1 (fr) |
WO (1) | WO1996038447A1 (fr) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5831096A (en) * | 1995-05-30 | 1998-11-03 | Rhone-Poulenc Rorer S.A. | L-tartaric acid salt of a (1R) diastereomer of a 2-azadihydroxybicyclo 2.2.1!heptane compound and the preparation of 2-azabicyclo 2.2.1! heptane compounds |
US5912365A (en) * | 1995-05-30 | 1999-06-15 | Rhone-Poulenc Rorer Sa | Derivatives of 2-azabicyclo 2.2.1! heptane, their preparation and their application |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2228163T3 (es) | 1998-12-31 | 2005-04-01 | Aventis Pharmaceuticals Inc. | Procedimiento para preparar derivados de desaza-adenosina n6-sustituidos. |
EP1574508A1 (fr) * | 2004-01-30 | 2005-09-14 | Lonza AG | Procédé pour la préparation d acetals et cétals de 3-amino-5-(hydroxymethyl)-cyclopentane -1,2-diols et leur derivés sels |
US8440709B2 (en) | 2005-12-14 | 2013-05-14 | Makhteshim Chemical Works Ltd. | Polymorphs and amorphous forms of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[(trifluoromethyl)sulfinyl]-1H-pyrazole-3-carbonitrile |
TWI677489B (zh) | 2014-06-20 | 2019-11-21 | 美商基利科學股份有限公司 | 多環型胺甲醯基吡啶酮化合物之合成 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4954504A (en) * | 1986-11-14 | 1990-09-04 | Ciba-Geigy Corporation | N9 -cyclopentyl-substituted adenine derivatives having adenosine-2 receptor stimulating activity |
EP0550631B1 (fr) * | 1990-09-25 | 1997-01-02 | Rhone-Poulenc Rorer International (Holdings) Inc. | Composes possedant des proprietes anti-hypertensives et anti-ischemiques |
-
1995
- 1995-05-30 FR FR9506353A patent/FR2734822B1/fr not_active Expired - Fee Related
- 1995-06-07 US US08/476,156 patent/US5631383A/en not_active Expired - Fee Related
-
1996
- 1996-05-28 WO PCT/FR1996/000793 patent/WO1996038447A1/fr not_active Application Discontinuation
Non-Patent Citations (5)
Title |
---|
B.L. KAM ET AL., JOURNAL OF ORGANIC CHEMISTRY, vol. 46, 1981, EASTON US, pages 3268 - 3272, XP002014506 * |
J. CHEN ET AL., TETRAHEDRON LETTERS, vol. 30, no. 41, 1989, OXFORD GB, pages 5543 - 5546, XP002014505 * |
N. KATAGIRI ET AL., CHEMICAL AND PHARMACEUTICAL BULLETIN, vol. 39, no. 5, 1991, TOKYO JP, pages 1112 - 1122, XP002014503 * |
N. KATAGIRI ET AL., TETRAHEDRON LETTERS, vol. 30, no. 13, 1989, OXFORD GB, pages 1645 - 1648, XP002014504 * |
R.C. CERMAK ET AL., TETRAHEDRON LETTERS, vol. 22, no. 25, 1981, OXFORD GB, pages 2331 - 2332, XP002014507 * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5831096A (en) * | 1995-05-30 | 1998-11-03 | Rhone-Poulenc Rorer S.A. | L-tartaric acid salt of a (1R) diastereomer of a 2-azadihydroxybicyclo 2.2.1!heptane compound and the preparation of 2-azabicyclo 2.2.1! heptane compounds |
US5886192A (en) * | 1995-05-30 | 1999-03-23 | Rhone-Poulenc Rorer S.A. | L-tartaric acid salt of a (1R) diastereomer of a 2-azadihydroxybicyclo 2.2.1!heptane compound and the preparation of 2-azabicyclo 2.2.1!heptane compounds |
US5912365A (en) * | 1995-05-30 | 1999-06-15 | Rhone-Poulenc Rorer Sa | Derivatives of 2-azabicyclo 2.2.1! heptane, their preparation and their application |
EP0934268A1 (fr) * | 1996-10-16 | 1999-08-11 | Rhone-Poulenc Rorer Pharmaceuticals, Inc. | Procede de preparation d'un compose de 2-azadihydroxybicyclo 2,2,1]heptane et du sel d'acide tartrique l de ce compose |
EP0934268A4 (fr) * | 1996-10-16 | 2001-04-18 | Rhone Poulenc Rorer Pharma | Procede de preparation d'un compose de 2-azadihydroxybicyclo 2,2,1]heptane et du sel d'acide tartrique l de ce compose |
Also Published As
Publication number | Publication date |
---|---|
FR2734822A1 (fr) | 1996-12-06 |
FR2734822B1 (fr) | 1997-07-04 |
US5631383A (en) | 1997-05-20 |
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