Anti-inflammatory carboxy pregnane derivatives
AssigneeFlorida Agricultural and Mechanical University
InventorHenry J. Lee
Life of this patent
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Abstract
Compounds of the formula: ##STR1## wherein one X is COOR, CH.sub.2 COOR, CH(COOR).sub.2, CONHR, CH.sub.2 CONHR, or CN remaining X's are H, F, CH.sub.3, OH, COOR, CH.sub.2 COOR, CH(COOR).sub.2, CONHR, CH.sub.2 CONHR, or CN; Y is ##STR2## R is H, alkyl of 1-5 carbon atoms, or benzyl; R.sub.1 is CH.sub.2 OR.sub.3, COOR, or CONHR; R.sub.2 is H, OR.sub.3, or BR; R.sub.3 is H, COR.sub.4, or tetrahydropyranyl; R.sub.4 is alkyl of 1-5 carbon atoms or benzyl; R.sub.5 is H or COR.sub.4 ; represents a single or double bond; represents .alpha.-position, .beta.-position, or a mixture of .alpha.- and .beta.-positions; and --- represents .alpha.-position; and methods for preparing the same.
Claims26
The process for preparing a pregnane derivative substituted in the 6-position with an alkyl ester group which comprises:
- (1) reacting cortisol or prednisolone with formaldehyde and hydrogen chloride to produce (I) 17.alpha.,20,20,21-bis(methylenedioxy)-11.beta.-hydroxy-pregn-4-ene-3-one;
- (2) reacting (I) with ethylene glycol and pyridine hydrochloride to produce (II) 3,3-ethylenedioxy-17.alpha.,20,20,21-bis(methylenedioxy)-pregn-5-ene-11.be ta.-ol;
- (3) epoxidizing (II) by treatment with m-chloroperbenzoic acid to produce (III) 5,6.alpha.-epoxy-3,3-ethylenedioxy-17.alpha.,20,20,21-bis(methylenedioxy)- 5.alpha.-pregnan-11.beta.-ol;
- (4) reacting (III) with a solution an alkenylmagnesium halide of 2-5 carbon atoms to produce (IV) 3,3-ethylenedioxy-17.alpha.,20,20,21-bis(methylenedioxy)-6.beta.(alkenyl)- 5.alpha.-pregnane-5-11.beta.-diol;
- (5) reacting (IV) with potassium permanganate and sodium periodate to produce (V) 3,3-ethylene-dioxy-17.alpha.,20,20,21-bis(methylenedioxy)-6.beta.-carboxya lkyl-5.alpha.-pregnane-5,11.beta.-diol;
- (6) esterifying the carboxyalkyl group by reacting (V) with an alkylating agent and recovering (VI) 3,3-ethylenedioxy-17.alpha.,20,20,21-bis(methylenedioxy)-6.beta.-alkoxy-ca rbonylalkyl-5.alpha.-pregnane-5-11.beta.-diol;
- (7) reacting (VI) with sulfuric acid to produce (VII) 17.alpha.,20,20,21-bis(methylenedioxy)-6.beta.-alkoxycarbonyl-alkyl-5.alph a.-pregnan-3-one;
- and
- (8) reacting (VII) with activated magnesium silicate to produce (VIII) 11.beta.-hydroxy-6.beta.-alkoxycarbonylalkyl-17.alpha.,20,20,21-bis(methyl enedioxy)-pregn-4-en-3-one.
The process for preparing a pregnane derivative substituted in the 16-position which comprises:
- (1) reacting prednisolone with triethylorthoacetate to produce (I) prednisolone-17,21-ethylorthoacetate;
- (2) reacting (I) with sodium acetate buffer in methanol to produce (II) prednisolone 17-acetate;
- (3) reacting (II) with acetic anhydride in pyridine to produce (III) prednisolone-17,21-diacetate;
- (4) reacting (III) with potassium acetate in dimethylformamide to produce (IV) 16,17-dehydroprednisolone-21-acetate;
- (5) saponifying (IV) to produce (V) 16,17-dehydroprednisolone;
- (6) reacting (V) with 2,3-dihydropyran and pyridinium tosylate to produce (VI) 16,17-dehydroprednisolone-21-tetrahydropyran;
- and
- (7) reacting (VI) with a mixture of sodium methylate and dimethylmalonate to produce (VII) 21-tetrahydropyranyl-16-yl(dimethylmalonyl)-11.beta.-hydroxy-3,20-dioxo-1, 4-pregnadiene.
The process for preparing a pregnane derivative substituted in the 16-position which comprises:
- (1) reacting prednisolone with triethylorthoacetate to produce (I) prednisolone-17,21-ethylorthoacetate;
- (2) reacting (I) with sodium acetate buffer in methanol to produce (II) prednisolone 17-acetate;
- (3) reacting (II) with acetic anhydride in pyridine to produce (III) prednisolone-17,21-diacetate;
- (4) reacting (III) with potassium acetate in dimethylformamide to produce (IV) 16,17-dehydroprednisolone-21-acetate;
- and
- (5) reacting (IV) with potassium cyanide in dimethylsulfoxide to produce (V) 21-acetoxy-16.alpha.-cyano-11.beta.-hydroxy-3,20-dioxo-1,4-pregnadiene
The process for preparing a pregnane derivative substituted in the 21-position which comprises:
- (1) reacting 21-carboxy-11.beta.,17.alpha.,21-trihydroxy-3-one-1,4-pregnadiene with N,N'-dicyclohexylcarbodiamide, 1-hydroxybenzotriazole, and RNH.sub.2 wherein R is methyl, ethyl, n-propyl, or benzyl to produce (I) 21-carboxamide-11.beta.,17.alpha.,21-trihydroxy-3-one-1,4-pregnadiene wherein the carboxamide group has the formula --CONHR with R having the meaning given above;
- and
- (2) reacting (I) with manganese dioxode in tetrahydrofuran to produce (II) 21-carboxamide-11.beta.,17.alpha.-dihydroxy-3,20-dione-1,4-pregnadiene.
Carboxypregnane derivatives of the formula:
- ##STR11## wherein one X is COOR, CONHR, or CH.sub.2 CONHR;
- remaining X's are H, F, CH.sub.3, OH, COOR, CONHR, or CH.sub.2 CONHR;
- ##STR12## R is H, alkyl of 1-5 carbon atoms, or benzyl;
- R.sub.1 is CH.sub.2 OR.sub.3, COOR, or CONHR;
- R.sub.2 is H, OR.sub.3, or Br;
- R.sub.3 is H, COR.sub.4, or tetrahydropyranyl;
- R.sub.4 is alkyl of 1-5 carbon atoms or benzyl;
- R.sub.5 is H or COR.sub.4 ;
- . . . represents a single or double bond;
- .about. represents .alpha.-position, .beta.-position or a mixture of .alpha.- and .beta.-positions;
- and . . . represents .alpha.-position.
Dependencies are inferred from the claim text.