WO1995029150A1 - Synthese des prototypes des inhibiteurs de la renine - Google Patents

Synthese des prototypes des inhibiteurs de la renine Download PDF

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Publication number
WO1995029150A1
WO1995029150A1 PCT/IB1995/000257 IB9500257W WO9529150A1 WO 1995029150 A1 WO1995029150 A1 WO 1995029150A1 IB 9500257 W IB9500257 W IB 9500257W WO 9529150 A1 WO9529150 A1 WO 9529150A1
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WO
WIPO (PCT)
Prior art keywords
carbon atoms
alkyl
compound
mmol
methyl
Prior art date
Application number
PCT/IB1995/000257
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English (en)
Inventor
Stephen Hanessian
Original Assignee
Ciba-Geigy Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ciba-Geigy Ag filed Critical Ciba-Geigy Ag
Priority to PL95316677A priority Critical patent/PL316677A1/xx
Priority to EP95913311A priority patent/EP0756590A1/fr
Priority to AU20823/95A priority patent/AU2082395A/en
Priority to JP7527500A priority patent/JPH09512266A/ja
Publication of WO1995029150A1 publication Critical patent/WO1995029150A1/fr
Priority to NO963831A priority patent/NO963831L/no
Priority to FI963743A priority patent/FI963743A/fi

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/02—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from isocyanates with formation of carbamate groups

Definitions

  • This invention relates to the field of biological activity relating to enzymatic and similar specific chemical breakdown of angiotensinogen by scission to angiotensin-l, then to angiotensin-ll, which engages receptors initiating biological activity as is well known.
  • Renin inhibitors prevent the production of angiotensin-ll, a potent vasoconstrictor and therefore are potent antihypertensives.
  • angiotensinogen is first cleaved to provide a specific fragment (angiotensin I), then subcleaved to a second specific fragment (angiotensin II), which engages the appropriate receptor to initiate biological activity:
  • the present invention contemplates novel stereoselective chemical synthensis of compounds as of the general formula I
  • the background is that of stereospecific synthetic organic chemistry, a voluminous and ever expanding field, in which it is a full time occupation to keep abreast of general trends, especially in areas relating to human medical application.
  • a principal object of the invention is to develop novel compounds suitable as prototypes for renin inhibitors. It is a related principal object to synthesize said novel compounds by novel chemical processes. It is a subsidiary object to devise practical synthetic schemes to prepare the novel compounds. It is a further subsidiary object to prepare the novel com ⁇ pounds as stereoisomerically pure as practicable. It is a further object to characterize all the compounds so prepared as fully as possible. Other objects would be readily apparent to skilled practitioners in the art, from the following specification, appended claims, and accompanying schemes and figures.
  • the invention is directed to a chemical compound having the structure
  • R . is hydrogen, or hydrocarbylcarboxy wherein the hydrocarbyl entity is selected from the group consisting of alkyl of 1 to 6 carbon atoms or aralkyl of 7 to 10 carbon atoms, R 2 and R 3 or independently alkyl of 1 to 4 carbon atoms, R 4 is alkyl of 1 to 6 carbon atoms or a substituent of aliphatic character, R 5 is selected from aromatics, substituted aromatics and heteroaromatics, substituted or unsubstituted cycloalkyls, cycloalkenes having 3 to 8 carbon atoms, with substituents selected from alkyl, alkoxy of 3 to 10 carbon atoms and alkoxy derivatives , primary and secondary amides and alkyl derivatives. Alkyl derivatives of primary and secondary amides are, for example, primary and secondary carbamoylalkyl groups.
  • Substituents of aliphatic character are, for example, butyl, 2-morpholinoethyl or 2- carbamoyl-2-methyl-propyl.
  • Alkoxy derivatives are, for example, alkoxyalkoxy groups such as 3-methoxy-propyloxy.
  • R is preferably alkylcarboxy and the alkyl group has 1 to 6 carbon atoms.
  • a preferred compound is (1 'S,2S,3R,3'R,5S)-5-[(3'-Butylcarbamoyl)-1 'hydroxy-butyl]-3-methyl-2-phenyl-pyrrolidine- 1 -carboxylic acid tert-butyl ester.
  • Another preferred compound is (1'S,2S,3R,3'R,5S)-5-[(3'- Butylcarbamoyl)-1 'hydroxy-butyl]-3-methyl-2-phenyl-pyrrolidine.
  • R ⁇ is preferably aralkylcarboxy and the aralkyl group has 7 to 10 carbon atoms.
  • a preferred compound is (1 'S,2S,3R,3'R,5S)-5-[(3'-Butylcarbamoyl)- 1'hydroxy-butyl]-3-methyl-2-phenyl-pyrrolidine-1 -carboxylic acid benzyl ester.
  • Both A may be hydrogen, when R ⁇ is preferably alkylcarboxy and the aralkyl group has 1 to 7 carbon atoms.
  • a preferred compound is (2R,4S,5S,7R)-5-[[1 ,1-Dimethylethoxy)car- bonyl]amino]-4-hydroxy 2,7-dimethyl-8-phenyl octanioic acid butyl amide.
  • Another preferred compound is (2R,4S,5S,7R)-5-amino-4-hydroxy-2,7-dimethyl-8-phenyl octanoic acid butyl amide.
  • the invention is directed to processes of preparation of a first chemical compound of structure
  • n is 0-3 inclusive
  • A are either both hydrogen atoms or form a single carbon-nitrogen bond
  • Ri is hydrogen, or hydrocarbylcarboxy wherein said hydrocarbyl is selected from the group consisting of alkyl of 1 to 6 carbon atoms or aralkyl of 7 to 10 carbon atoms
  • R 2 and R 3 are independently alkyl of 1 to 4 carbon atoms
  • R is alkyl of 1 to 6 carbon atoms or a substituent of aliphatic character such as, for example, butyl, 2-morpholinoethyl or 2- carbamoyl-2-methyi-propyl
  • R 5 is selected from aromatics, substituted aromatics and heteroaromatics, substituted or unsubstituted cycloalkyls, cycloalkenes having 3 to 8 carbon atoms, with substituents selected from alkyl, alkoxy or 3 to 10 carbon atoms and alkoxy derivatives such as 3- ethoxy-propyl
  • the processes include a step selected from the group consisting of (a) hydrogenolysis of a second compound of the above formula wherein both A together form a single carbon nitrogen bond and Ri is alkylcarboxy wherein said alkyl has 1 to 6 carbon atoms, in the presence of Pd(OH)2/C; (b) hydrogenolysis of a third compound of the above formula wherein both A together form a single carbon nitrogen bond and R is aralkylcarboxy wherein said aralkyl has 7 to 10 carbon atoms, in the presence of Pd(PH) 2 /C, and dialkyl dicarbonate wherein both said dicarbonate alkyl groups are identical and have 1 to 6 carbon atoms; and (c) treating a fourth compound having the structure
  • Ri is hydrocarbylcarboxy wherein said hydrocarbyl is selected from the group consisting of alkyl of 1 to 6 carbon atoms or aralkyl of 7 to 10 carbon atoms, R 2 and R 3 are independently alkyl of 1 to 4 carbon atoms, with R 4 NHAIMe 2 where R 4 is alkyl of 1 to 6 carbon atoms.
  • n is zero, in both formulae.
  • a preferred process of claim 14, comprises the step of hydrogenolysis of said second compound.
  • Another preferred process comprises the step of hydrogenolysis of said third compound.
  • a further preferred process comprises the step of treating said fourth compound, where in a preferred step Ri is alkyl ⁇ carboxy, said alkyl group having 1 to 6 carbon atoms.
  • Ri may be aralkylcar ⁇ boxy, said aralkyl having 7 to 10 carbon atoms.
  • Scheme 1 indicates a first synthetic route of the invention
  • 17a was hydrogenated saturating the double furan/lactone bond to give 93 % yield of 18a as a mixture of two rotamers.
  • the saturated lactone ring of 18a was methylated, 67 % of the desired mono- methyl 19a, and 15 % of the dimethyl lactone were obtained.
  • Crystalline 19a was X-ray analyzed.
  • the lactone ring was opened by formation of the butyl amide to give 2a in 76 % yield. Then the pyrrolodine ring was hydrogenolyzed to give 3a in 73 % yield.
  • This route is generally analogous to scheme 2, starting with cyclized imine 14, and protecting the imino nitrogen with a carboxybenzyl group rather than a carboxybutyl group, to yield 67 % (from 13) of 15b as a mixture of anomers and rotamers. Thereafter the steps are closely similar giving 89 % of 16b, 78 % of 17b, as 5:1 threo:erythro isomeric ratio. Pure erythro 17b was crystallized as a mixture of rotamers. Crystalline 17b was X-ray analyzed. Continuing gave 90 % of 18b, 56 % of 19b, 52 % of 2b, which was directly converted to 3a, in 46 % yield.
  • the reaction was stirred at -78°C for 2 h and then quenched with 15 mL of 1 :15 % aqueous NH 4 OH and saturated aqueous NH CI solution. The cooling bath was removed and the reaction allowed to warm to room temperature. Aqueous 10 % NH 4 OH (50 mL) and ether (300 mL) were then added and the resulting mixture was stirred until a homogenous organic phase and a dark blue aqueous phase were obtained.
  • Triphenylphosphine (5.33 g, 20.3 mmol) was added to the solution of 2.82 g (13.56 mmol) of the hydroxyester 9 in 70 mL of anhydrous THF and cooled to 0°C. DEAD was added dropwise followed by the dropwise addition of (PhO) 2 P(O)N 3 . The reaction was gradually allowed to warm to room temperature overnight.
  • reaction mixture was quenched with a solution of AcOH (0.15 mL) in 0.4 mL anhydrous THF and allowed to warm to temperature, then diluted with EtOAc, washed with water, brine, dried over MgSO 4 and concentrated. Purification of the residue by column chromatography (silica gel.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pyrrole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

Prototypes d'inhibiteurs de la rénine ayant la structure générale (I) dans laquelle n vaut de 0 à 3 inclus, A représente soit deux atomes d'hydrogène, soit une liaison simple carbone-azote; R1 représente hydrogène ou hydrocarbylcarboxy où l'entité hydrocarbyle est sélectionnée dans le groupe comprenant alkyle de 1 à 6 atomes de carbone ou aralkyle de 7 à 10 atomes de carbone, R2 et R3 représentent, indépendamment, alkyle de 1 à 4 atomes de carbone, R4 représente alkyle de 1 à 6 atomes de carbone ou un substituant de caractère aliphatique tel que, par exemple, butyle, 2-morpholinoéthyle ou 2-carbamoyle-2-méthyle-propyle, R5 est sélectionné parmi des composés aromatiques, des composés aromatiques et hétéroaromatiques substitués, des cycloalkyles substitués ou non substitués, des cycloalcènes possédant de 3 à 8 atomes de carbone, lesdits substituants étant sélectionnés entre alkyle, alcoxy de 3 à 10 atomes de carbone, et des dérivés d'alcoxy, tels que 3-méthoxy-propyloxy, des amides primaires et secondaires et des dérivés d'alkyle. Ces prototypes sont préparés à l'aide d'une nouvelle synthèse à plusieurs étapes. Ces composés sont des produits intermédiaires précieux utilisés dans la fabrication de produits pharmaceutiques, tels que des inhibiteurs de la rénine et des inhibiteurs de la protéase du VIH.
PCT/IB1995/000257 1994-04-21 1995-04-12 Synthese des prototypes des inhibiteurs de la renine WO1995029150A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
PL95316677A PL316677A1 (en) 1994-04-21 1995-04-12 Synthesis of prototypes for renin inhibitors
EP95913311A EP0756590A1 (fr) 1994-04-21 1995-04-12 Synthese des prototypes des inhibiteurs de la renine
AU20823/95A AU2082395A (en) 1994-04-21 1995-04-12 Synthesis of prototypes for renin inhibitors
JP7527500A JPH09512266A (ja) 1994-04-21 1995-04-12 レニン阻害剤に対するプロトタイプの合成
NO963831A NO963831L (no) 1994-04-21 1996-09-13 Syntese av prototyper for renin-inhibitorer
FI963743A FI963743A (fi) 1994-04-21 1996-09-20 Reniini-inhibiittorien prototyyppien synteesi

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CA2,121,898 1994-04-21
CA002121898A CA2121898A1 (fr) 1994-04-21 1994-04-21 Synthese de prototypes d'inhibiteurs de la renine

Publications (1)

Publication Number Publication Date
WO1995029150A1 true WO1995029150A1 (fr) 1995-11-02

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PCT/IB1995/000257 WO1995029150A1 (fr) 1994-04-21 1995-04-12 Synthese des prototypes des inhibiteurs de la renine

Country Status (12)

Country Link
EP (1) EP0756590A1 (fr)
JP (1) JPH09512266A (fr)
CN (1) CN1147810A (fr)
AU (1) AU2082395A (fr)
CA (1) CA2121898A1 (fr)
CZ (1) CZ306596A3 (fr)
FI (1) FI963743A (fr)
HU (1) HUT74743A (fr)
IL (1) IL113401A0 (fr)
PL (1) PL316677A1 (fr)
WO (1) WO1995029150A1 (fr)
ZA (1) ZA953187B (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003067986A1 (fr) * 2002-02-13 2003-08-21 Bayer Cropscience Ag $g(d)1-pyrrolines et leur utilisation dans la lutte antiparasitaire

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0511686D0 (en) * 2005-06-08 2005-07-13 Novartis Ag Organic compounds
CN109422664B (zh) * 2017-08-23 2022-02-18 中国科学院福建物质结构研究所 一类干扰素调节剂及其制备方法和用途

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
A. BASHA ET AL.: "A mild, general method for conversion of esters to amides", TETRAHEDRON LETTERS, vol. 48, 1977, OXFORD GB, pages 4171 - 4174 *
APPL. CATAL., A, vol. 100, no. 1, 1993, pages 145 - 155 *
CHEMICAL ABSTRACTS, vol. 119, no. 15, 11 October 1993, Columbus, Ohio, US; abstract no. 159472, TRIYONO; R. KRAMER page 848; *
S. HANRSSIAN, S. RAGHAVAN: "Design and synthesis of a prototypical, non-peptidic inhibitor model for the enzyme renin", BIORG. MED. CHEM. LETT., vol. 4, no. 14, 1994, pages 1697 - 1702 *
Y. MORIMOTO ET AL.: "An efficient approach towards pyrrolidinyllactone system characteristic of the stemona alkaloid.", TETRAHEDRON LETTERS, vol. 34, no. 36, 1993, OXFORD GB, pages 5773 - 5776 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003067986A1 (fr) * 2002-02-13 2003-08-21 Bayer Cropscience Ag $g(d)1-pyrrolines et leur utilisation dans la lutte antiparasitaire

Also Published As

Publication number Publication date
FI963743A0 (fi) 1996-09-20
IL113401A0 (en) 1995-07-31
CA2121898A1 (fr) 1995-10-22
HU9602892D0 (en) 1996-12-30
JPH09512266A (ja) 1997-12-09
HUT74743A (en) 1997-02-28
CZ306596A3 (en) 1997-01-15
ZA953187B (en) 1995-10-23
PL316677A1 (en) 1997-02-03
FI963743A (fi) 1996-09-20
EP0756590A1 (fr) 1997-02-05
CN1147810A (zh) 1997-04-16
AU2082395A (en) 1995-11-16

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