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WO1997011936A1 - Preparation de derives de carboxyalkyle - Google Patents

Preparation de derives de carboxyalkyle Download PDF

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Publication number
WO1997011936A1
WO1997011936A1 PCT/US1996/015672 US9615672W WO9711936A1 WO 1997011936 A1 WO1997011936 A1 WO 1997011936A1 US 9615672 W US9615672 W US 9615672W WO 9711936 A1 WO9711936 A1 WO 9711936A1
Authority
WO
WIPO (PCT)
Prior art keywords
6alkyl
substituted
aryl
hydroxy
alkyl
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/US1996/015672
Other languages
English (en)
Inventor
Mitree M. Ponpipom
William K. Hagmann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck and Co Inc
Original Assignee
Merck and Co Inc
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
Priority claimed from GBGB9603572.0A external-priority patent/GB9603572D0/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Priority to AU73811/96A priority Critical patent/AU7381196A/en
Publication of WO1997011936A1 publication Critical patent/WO1997011936A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/16—Preparation of optical isomers
    • C07C231/18—Preparation of optical isomers by stereospecific synthesis

Definitions

  • Stromelysin aka. proteoglycanase, matrix metal loproteinase-3 (MMP-3), procollagenase activator, "transin”
  • collagenase aka. interstitial collagenase, matrix metalloproteinase- 1 (MMP-1)
  • gelatinase aka.
  • type IV collagenase, matrix metal loproteinase-2 (MMP-2), 72kDa-gelatinase or type V collagenase, matrix metal loproteinase-9, (MMP-9), 92kDa-gelatinase) are metalloendoproteinases secreted by fibroblasts and chondrocytes, and are capable of degrading the major connective tissue components of articular cartilage or basement membranes. See G.M. McGeehan et al., Nature 370. 558 (94); A.J.H Gearihg et al., Nature 37Q, p555 (94); K.M. Mohler et al., Nature 370, p218 (94) and EP274,234.
  • OA osteoarthritis
  • RA rheumatoid arthritis
  • DMARD's Disease modifying antirheumatic drugs
  • NSAIDs Generic nonsteroidal antiinflammatory drugs
  • Stromelysin and collagenase inhibitors are also believed to have utility in preventing articular cartilage damage associated with septic arthritis, controlling tumor metastasis, optionally in combination with current chemotherapy and/or radiation. See L.M. Matrisian, G.T. Bowden, P. Krieg, G. Furstenberger, J.P. Briand, P. Leroy, R. Breathnach, "The mRNA coding for the secreted protease transin is expressed more abundantly in malignant than in benign tumors", Proc. Natl. Acad. Sci.. USA. 83, 9413-7 (1986); S.M. Wilhelm, I.E. Collier, A. Kronberger, A.Z. Eisen, B.L. Manner, G.A.
  • the inhibitors described in Scheme I are prepared as follows. An arylalkyl carboxylic acid is first converted to its corresponding acid chloride using oxallyl chloride and this is used to acylate lithio-4-benzyl-2-oxazolidinone. The derived imide is then enolized with Cl3Ti(Oi-Pr) in the presence of Hunig's base and alkylated with t-butyl acrylate. The chiral auxilliary is then remove with lithium hydroperoxide and the resulting acid ester enolized with lithium diisoprpyl amide and alkylated with an alkyl halide.
  • This invention is concemed with a novel process for the preparation of carboxyalkyl derivatives of Formula I (wherein R l , R2, R3, AA and X are described below) which are useful inhibitors of matrix metalloendoproteinase-mediated diseases including degenerative diseases (such as defined above) and certain cancers.
  • the instant process offers selectivity in the alkylation step by not producing isomeric products that require column chromatography for
  • the instant invention encompasses the process of making a compound of Formula I
  • Rl is hydrogen, mono or disubstituted Ci-Ralkyl, C ⁇ _6alkoxy or substituted C2-8 alkenyl wherein the substituents are independently selected from the group consisting of:
  • Aryl wherein the Aryl group is selected from the group consisting of
  • Ra and Rb are each independently hydrogen; Aryl or heteroaryl and mono and di-substituted aryl or heteroaryl as defined above; or substituted C l -6alkyl wherein the substitutent is selected from hydroxy, halo, and aryl or heteroaryl, or wherein Ra and Rb are joined such that together with the nitrogen and carbon atoms to which they are attached, there is formed a saturated or unsaturated Iactam or benzolactam ring such as wherein n is 1 , 2 or 3 or benzo fused Iactam ring such as
  • the Iactam portion thereof is a ring of 5, 6, 7 or 8 atoms, said Iactam or benzolactam to have a single hetero atom;
  • R a and Rb are each independently hydrogen; aryl or heteroaryl and mono and di-substituted aryl or heteroaryl as defined above; or substituted C i-6alkyl wherein the substitutent is selected from hydroxy, halo, and aryl, or wherein R a and Rb are joined such that together with the nitrogen and carbon atoms to which they are attached, there is formed a saturated or unsaturated lactim (or imide) such as
  • lactim portion thereof is a ring of 5, 6, 7 or 8 atoms, said lactim or benzolactim to have a single hetero atom;
  • Ra and Rb are each independently hydrogen; or Cl-6 Alkyl; aryl as defined above or ArylC ⁇ -6Alkyl or mono or di substituted ArylC ⁇ -6Alkyl wherein the substitutents are independently selected from Cl-6alkyl, Cl-6alkyloxy, halo, hydroxy, amino, Cl-6alkylamino, aminoCl-6alkyl, carboxyl, carboxylCl-6alkyl, and Cl-6 alkylcarbonyl and Aryl is defined above; or wherein Ra and Rb are joined such that together with the nitrogen and oxygen atoms to which they are attached, there is formed a saturated or unsaturated monocyclic urethane or benzofused cyclic urethane such as
  • urethane ring contains 5, 6, 7 or 8 atoms, said ring to contain 2 heteroatoms
  • R a , Rb, and R c are each independently hydrogen; or Cl-6 Alkyl; or ArylC ⁇ -6 Alkyl or mono or di substituted ArylC ⁇ -6Alkyl wherein the substitutents are independently selected from C ⁇ _6alkyl, Ci -6alkyloxy, halo, hydroxy, amino, Cl-6alkylamino, aminoCi -6alkyl, carboxyl, carboxylCi_6alkyl, and C i -6alkylcarbonyl and aryl is defined as above; or wherein R and Rb are joined such that together with the nitrogen atoms to which they are attached, there is formed a saturated or unsaturated monocyclic urea or benzofused cyclic urea such as
  • urea ring contains up to 8 atoms, said ring to contain 2 heteroatoms; or Rb and Rc are joined such that together with the nitrogen atom to which they are attached, there is formed a saturated or unsaturated monocyclic ring or benzofused ring containing 5, 6, 7 or 8 atoms, said ring to contain 1 heteroatom;
  • Ra and Rb are each independently hydrogen; or Cl-6
  • sulfonamide ring contains 5, 6, 7 or 8 atoms, said ring to contain 2 heteroatoms;
  • Ra and Rb are each independently hydrogen; or Cl -6
  • Ra and Rb are each independently hydrogen; or Cl -6
  • R2 is Cl- 12 alkyl, arylCl-4alkyl, aryl substituted Ci -4alkyl, (arylCi-
  • aryl group is selected from the group consisting of:
  • Z is a pharmaceutically counterion, such as sodium, potassium, calcium or magnesium
  • substituted phenyl wherein the substitutent is carboxy, carboxyC l -3alkyl, aminocarbonyl, C l -6alkylaminocarbonyl;
  • AA is a single bond or an amino acid of formula II
  • Rf and Rg are individually selected from:
  • X is 6 wherein R5 and R6 are each individually selected from the group consisting of:
  • the unsaturated rings such as those described in definitions R l (d), (e), (g), (h), (i), (j) and (k) are intended to include rings wherein a double bond is present at one, two or more of the available positions.
  • the term aryl C ⁇ -6 alkyl as found in definitions such as Rl (g), (h), (i), (j) and (k) are intended to describe aryl and aryl Cl-6 alkyl.
  • aryl Cl -4 alkyl- aryl Cl -4 arkyl
  • aryl Cl-4 alkyl group wherein the aryl is substituted as aryl Cl-4 alkyl- such as -CH2 phenyl.
  • Ri , R 2 AA, and X are as described herein
  • Preparation of compound 14 comprises adding to a solution containing solvents, belonging to a group consisting of dichloromethane, benzene, toluene, cyclohexane, heptane, EDC, or other carbodiimides, and the like, a carboxylic acid of the formula (9):
  • a preferred process of the invention encompasses the process of making a compound of formula I
  • Rl is substituted Cl -8 alkyl
  • R2 is Cl-12 alkyl, arylC l -4alkyl, aryl substituted Cl -4alkyl, (arylCi-4alkyl)-arylCi-4alkyl, or biarylC ⁇ oalkyl wherein the substituent is Cl -3alkyl or hydroxy, and wherein the aryl group is selected from the group consisting of:
  • R3 is (a) H
  • substituted phenyl wherein the substitutent is carboxy, carboxyC 1 -3 alkyl, aminocarbonyl, C l -6alkylaminocarbonyl;
  • AA is a single bond or an amino acid of formula II
  • Rf and Rg are individually selected from
  • X is 6 wherein R5 and R6 are each individually selected from the group consisting of:
  • Lithium aluminum hydride (20.2 mL; 1.0 M in THF) was added to a stirred solution of (1) (3.84 g, 20.2 mmol) in THF (20 mL) at 0 °C. The solution was stirred at room temperature for 2 h and quenched sequentially with water (0.77 mL), 15% NaOH (0.77 mL), and water (2.3 mL). The resulting suspension was filtered, and the filtrate was evaporated to dryness. The residue was partitioned between CH2CI2 and brine, and the organic layer was separated, dried, and concentrated to a liquid (2.29 g, 70%):
  • EXAMPLE (6) L-Prolinol 4-(n-Propyl phenylbutanamide l -(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC; 5.58 g, 29.1 1 mmol) was added to a solution of 4- (t ⁇ -propyl)phenylbutanoic acid (5.0 g, 24.24 mmol) and (5)-2- pyrrolidinemethanol (L-prolinol; 2.39 mL, 24.35 mmol) in dichloromethane (30 mL), and the reaction mixture was stirred at room temperature overnight.
  • EDC n-Propyl phenylbutanamide l -(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • the reaction mixture was stirred at this temperature for 3 h and at room temperature for 2 h over which time the dark red color faded to a pale yellow color.
  • the reaction was quenched with saturated ammonium chloride (200 mL). The two layers were separated, and the aqueous layer was back extracted with CH2CI2 (2 x). The combined organic extracts were washed with aqueous NaHC ⁇ 3, brine, dried, and evaporated to a yellow oil.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

On a découvert que les composés carboxy-peptidyle de la formule (I) sont des inhibiteurs utiles de maladies induites par des métalloendoprotéinases matricielles, en particulier de l'ostétoarthrite, de la polyarthite rhumatoïde, de l'arthrite aigue suppurée, des tumeurs invasives dans certains cancers, des paradontolyses, des ulcérations de la cornée, de la protéinurie, de l'épidermolyse bulleuse dystrophique, des thromboses coronaires associées à la rupture des plaques athéroscléreuses et des anévrismes de l'aorte. L'invention concerne un procédé de production de composés carboxy-peptidyle de la formule (I).
PCT/US1996/015672 1995-09-28 1996-09-24 Preparation de derives de carboxyalkyle Ceased WO1997011936A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU73811/96A AU7381196A (en) 1995-09-28 1996-09-24 Preparation of carboxyalkyl derivatives

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US527295P 1995-09-28 1995-09-28
US60/005,272 1995-09-28
GB9603572.0 1996-02-20
GBGB9603572.0A GB9603572D0 (en) 1996-02-20 1996-02-20 Preparation of carboxyalkyl derivatives

Publications (1)

Publication Number Publication Date
WO1997011936A1 true WO1997011936A1 (fr) 1997-04-03

Family

ID=26308768

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1996/015672 Ceased WO1997011936A1 (fr) 1995-09-28 1996-09-24 Preparation de derives de carboxyalkyle

Country Status (2)

Country Link
AU (1) AU7381196A (fr)
WO (1) WO1997011936A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4374847A (en) * 1980-10-27 1983-02-22 Ciba-Geigy Corporation 1-Carboxyalkanoylindoline-2-carboxylic acids
US4479963A (en) * 1981-02-17 1984-10-30 Ciba-Geigy Corporation 1-Carboxyalkanoylindoline-2-carboxylic acids

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4374847A (en) * 1980-10-27 1983-02-22 Ciba-Geigy Corporation 1-Carboxyalkanoylindoline-2-carboxylic acids
US4479963A (en) * 1981-02-17 1984-10-30 Ciba-Geigy Corporation 1-Carboxyalkanoylindoline-2-carboxylic acids

Also Published As

Publication number Publication date
AU7381196A (en) 1997-04-17

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