US3812166A - Dichloro-substituted estradiene - Google Patents

Dichloro-substituted estradiene Download PDF

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US3812166A
US3812166A US00853480A US85348069A US3812166A US 3812166 A US3812166 A US 3812166A US 00853480 A US00853480 A US 00853480A US 85348069 A US85348069 A US 85348069A US 3812166 A US3812166 A US 3812166A
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acid
estradiene
dichloro
methyl
ethinyl
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R Wiechert
H Steinbeck
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Bayer Pharma AG
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Schering AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J75/00—Processes for the preparation of steroids in general

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  • the 4-unsubstituted 6-chloroestradiene is subjected to the action of an agent furnishing positive and negative chlorine, thereby forming the 6,6,7-trichloro-substituted compound, followed by treatment of the latter compound with a base.
  • the compounds have a very high progesterone activity.
  • the compounds of the invention are racemic or optically active 4,6-dichloro-4,6-estradienes of the formula in in wherein R is hydrogen, alkyl, tetrahydropyranyl or an 7 acid residue.
  • the invention also embraces a process for making these compounds by subjecting a 6-chloro-4,6-estradiene of the formula wherein R has the same meaning as given above, to the action of an agent adapted to furnish positive and negative chlorine, thereby forming the 6,6,7-trichloro compound and then treating the trichloro compound with a. base.
  • the invention also includes pharmaceutical compositions in which the defined compounds are the active agents.
  • the invention furthermore includes a process of treatment of gynecological afflictions by applying the pharmaceutical compositions just mentioned to a patient requiring such treatment.
  • R is an acid residue, it may be formed by any physiologically compatible and acceptable acids.
  • Preferred acids are carboxylic acids having 11p to 15 carbon atoms.
  • the carboxylic acids can also be unsaturated, branched, polyhydroxylic or can be substituted in conventional manner, for instance by hydroxyl or amino groups or halogen -atoms.
  • Suitable also are cycloaliphatic, aromatic, mixed aromatic-aliphatic or heterocyclic acids which likewise may be substituted in conventional manner.
  • Suitable acids are for instance the following: acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, undecylic acid, trimethylacetic acid, diethylacetic acid, t-butylacetic acid, phenylacetic acid, cyclopentylpropionic acid, oleic acid, lactic acid, mono-, diand trichloroacctic acid, aminoacetic acid, succinic acid, adipic acid, benzoic acid, nicotinic acid.
  • the conventional inorganic acids such as sulfuric and phosphoric acid may also be used.
  • Alkyl preferably is methyl, ethyl, propyl or butyl.
  • compositions containing the compounds of the invention as the effective agent is in the treatment of the following gynecological afilictions: primary amenorrhea and secondary amenorrhea of extended duration, cycle irregularities in case of inadequate function of the corpus luteum, endometriosis, uteras hypoplasia, premenstrual complaints, mastopathy, etc.
  • the dosage depends on the severity of the illness. Generally, it is advisable to administer between 5 and mg. of eiiective agent per day. Serious menstruation irregularities can for instance be corrected by a cycle corresponding treatment with daily doses of 10 mg. of eifective agent. In the case of certain indications such as dysfunctional bleeding or medically advised anticonceptive treatment, the
  • compositions including the effective agents may be prepared in conventional manner, for instance by incorporating the compounds of the invention together with the conventional additives as used in galenic pharmacy, carrier materials and flavoring agents in any desired application form such as tablets, lozenges, capsules, pills, suspensions or solutions.
  • an orally administered tablet should preferably contain 0.1 to mg. of effective agent.
  • a solution for parenteral application should preferably contain from 1 to 20 mg./ml. of solution.
  • the parenteral application includes all possible types of administration such as subcutaneous, intramuscular and intravenous administration.
  • Tablets may for instance have the following composition:
  • racemic (rac) and optically active (nat.) 4,6-dichloro-4,6-estraidenes of the above given formula (I) may be formed, for instance, as follows:
  • the starting product is a 6-chloro-4,6-estradiene of the formula wherein R is hydrogen, alkyl, tetrahydropyranyl or an acid residue. These compounds are subjected to the action of an agent furnishing positive and negative chlorine so as to form the 6,6,7-trichloro compound. The latter compound is then treated with a base. Depending on the desired character of R and the starting compound employed (in respect of R), an esterified or etherified hydroxyl group may then be subjected to hydrolysis or, if a free hydroxyl group is present, the latter group may be esterified or etherified.
  • Positive and negative chlorine may be obtained during the reaction from suitable chlorine-containing compounds.
  • Positive chlorine for instance is obtained from N-chloroacylamides or -acylimides, preferably N-chloro-acetamide or N-chloro-succinimide.
  • hypochlorites may also be used, such as tert. butylhypochlorite.
  • Agents furnishing negative chlorine are for instance chlorides, preferably lithium chloride.
  • a steroid of the formula given above for the starting compounds may be dissolved in acetic acid and then subjected to the action of lithium chloride and N-chlorosuccinimide in the presence of a strong anhydrous acid such as hydrochloric acid in dioxane or tetrahydrofuran.
  • a strong anhydrous acid such as hydrochloric acid in dioxane or tetrahydrofuran.
  • the corresponding 6,6,7-trichloro compound is then formed by chlorination of the A -double bond.
  • the trichloro compound is thereafter treated, preferably with an organic base, to split off hydrogen chloride.
  • the splitting off of the hydrogen chloride is accompanied by a migration of the chlorine atom to the 4-position.
  • Chlorination and hydrogen chloride elimination take place under mild conditions, preferably at temperatures around room temperature.
  • a reaction may be chosen with an acid anhydride or acid halide in the presence of an acidic or basic agent or the reaction may be carried out with the desired free acid in the presence of trifluoroacetic acid anhydride.
  • the 17-carboxylic acid esters For the purpose of the saponification, it is preferable to subject the 17-carboxylic acid esters to the action of a base, for instance an alkali hydroxide, alcoholate or alkali carbonate in the presence of water, preferably an alcoholic solution and, if desired, upon addition of a solution promoting agent.
  • a base for instance an alkali hydroxide, alcoholate or alkali carbonate
  • water preferably an alcoholic solution and, if desired, upon addition of a solution promoting agent.
  • the 17-hydroxy compound can be reacted with dihydropyran in the presence of an acid such as p-toluenesulfonic acid.
  • the etherification with an alkyl residue preferably is effected with an alkyl halide in the presence of a basic condensation agent such as silver oxide.
  • the 6u,7a-epoxide is formed with m-chloroperbenzoic acid and the epoxide is then treated with hydrogen chloride in acetic acid at room temperature.
  • the resulting rac.-6 8-chloro-7a-hydroxy-17B-acetoxy 18 methyl-17aethinyl-4-estrene-3-one is converted to the 7-mesylate with methane sulfonic acid chloride in pyridine.
  • the 6u,7a-epoxide is formed with m-chloroperbenzoic acid.
  • EXAMPLE 3 1.9 g. of nat.-6-chloro-17/3-hydroxy-18methyl-17a-ethinyl-4,6-estradiene-3-one are dissolved in 300 ml. acetic acid and successively reacted with 10 g. of lithium chloride, 1.9 g. of N-chlorosuccinimide and 0.4 ml. dioxane/ HCl. After a reaction time of 7 minutes at room temperature, the subsequent treatment is started and carried out as in Example 1.
  • estradiene of claim 1 wherein alkyl is methyl, ethyl, propyl or butyl.
  • estradiene of claim 1 wherein the acid residue is formed of a carboxylic acid having up to 15 carbon atoms.
  • estradiene of claim 1 which is rac.-4,6-dichloro- 17,8-acetoxy-18-methyl-l7a-ethinyl-4,6-estradiene-3-one.
  • estradiene of claim 1 which is nat.-4,6-dichloroacetoxy-l8-methyl-17a-ethinyl-4,6-estradiene-3-one.
  • estradiene of claim 1 which is nat.-4,6-dichloro- 17,9 hydroxy-18-methyl-17a-ethinyl-4,6-estradiene-3-one.
  • estradiene of claim 1 which is nat.-4,6-dichloro- 117,8 heptanoyloxy-lS-methyl-17u-ethinyl-4,6-estradiene- -one.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

A RACEMIC OR OPTICALLY ACTIVE, 4,6-DICHLORO-4,6-ESTRADIENE OF THE FORMULA

4,6-DI(CL-),17-(R-O-),17-(CH*C-),18-CH3-ESTRA-4,6-DIEN-

3-ONE

WHEREIN R IS HYDROGEN, ALKYL, TETRADROPYRANYL OR AN ACID RESIDUE. TO FORM THE COMPOUNDS, THE 4-UNSUBSTITUTED 6-CHLOROESTRADIENE IS SUBJECTED TO THE ACTION OF AN AGENT FURNISHING POSITIVE AND NEGATIVE CHLORINE, THEREBY FORMING THE 6,6,7-TRICHLORO-SUBSTITUTED COMPOUND, FOLLOWED BY TREATMENT OF THE LATTER COMPOUND WITH A BASE. THE COMPOUNDS HAVE A VERY HIGH PROGESTERONE ACTIVITY.

Description

United States Patent 3,812,166 DICHLORO-SUBSTITUTED ES'I'RADIENE Rudolf Wiechert and Hermann Steinbeck, Berlin, Germany, assignors to Schering Aktiengesellschaft, Berlin and Bergkamen, Germany No Drawing. Filed Aug. 27, 1969, Ser. No. 853,480 Claims priority, application Germany, Sept. 13, 1968, P 17 93 422.4 Int. Cl. C07c 169/22 US. Cl. 260-3974 14 Claims ABSTRACT OF THE DISCLOSURE A racemic or optically active, 4,6-dichloro-4,6-estradiene of the formula wherein R is hydrogen, alkyl, tetrahydropyranyl or an acid residue.
To form the compounds, the 4-unsubstituted 6-chloroestradiene is subjected to the action of an agent furnishing positive and negative chlorine, thereby forming the 6,6,7-trichloro-substituted compound, followed by treatment of the latter compound with a base.
The compounds have a very high progesterone activity.
BACKGROUND OF THE INVENTION SUMMARY OF THE INVENTION The compounds of the invention are racemic or optically active 4,6-dichloro-4,6-estradienes of the formula in in wherein R is hydrogen, alkyl, tetrahydropyranyl or an 7 acid residue.
ice
The invention also embraces a process for making these compounds by subjecting a 6-chloro-4,6-estradiene of the formula wherein R has the same meaning as given above, to the action of an agent adapted to furnish positive and negative chlorine, thereby forming the 6,6,7-trichloro compound and then treating the trichloro compound with a. base.
The invention also includes pharmaceutical compositions in which the defined compounds are the active agents.
The invention furthermore includes a process of treatment of gynecological afflictions by applying the pharmaceutical compositions just mentioned to a patient requiring such treatment.
DESCRIPTION OF THE PREFERRED EMBODIMENTS If R is an acid residue, it may be formed by any physiologically compatible and acceptable acids. Preferred acids are carboxylic acids having 11p to 15 carbon atoms. The carboxylic acids can also be unsaturated, branched, polyhydroxylic or can be substituted in conventional manner, for instance by hydroxyl or amino groups or halogen -atoms. Suitable also are cycloaliphatic, aromatic, mixed aromatic-aliphatic or heterocyclic acids which likewise may be substituted in conventional manner. Examples of suitable acids are for instance the following: acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, undecylic acid, trimethylacetic acid, diethylacetic acid, t-butylacetic acid, phenylacetic acid, cyclopentylpropionic acid, oleic acid, lactic acid, mono-, diand trichloroacctic acid, aminoacetic acid, succinic acid, adipic acid, benzoic acid, nicotinic acid. The conventional inorganic acids such as sulfuric and phosphoric acid may also be used.
Alkyl preferably is methyl, ethyl, propyl or butyl.
UTILITY The 4,6-dichloro-4,6-estradienes of the invention have a surprisingly high progesterone action. In view of the literature above cited, this could not be expected.
The main application of the pharmaceutical compositions containing the compounds of the invention as the effective agent is in the treatment of the following gynecological afilictions: primary amenorrhea and secondary amenorrhea of extended duration, cycle irregularities in case of inadequate function of the corpus luteum, endometriosis, uteras hypoplasia, premenstrual complaints, mastopathy, etc.
The dosage depends on the severity of the illness. Generally, it is advisable to administer between 5 and mg. of eiiective agent per day. Serious menstruation irregularities can for instance be corrected by a cycle corresponding treatment with daily doses of 10 mg. of eifective agent. In the case of certain indications such as dysfunctional bleeding or medically advised anticonceptive treatment, the
0 compounds of the invention may also be administered in Pharmaceutical compositions including the effective agents may be prepared in conventional manner, for instance by incorporating the compounds of the invention together with the conventional additives as used in galenic pharmacy, carrier materials and flavoring agents in any desired application form such as tablets, lozenges, capsules, pills, suspensions or solutions.
The concentration of effective agents in all these various types of pharmaceutical compositions depends on the kind of administration. For instance, an orally administered tablet should preferably contain 0.1 to mg. of effective agent. A solution for parenteral application should preferably contain from 1 to 20 mg./ml. of solution. The parenteral application includes all possible types of administration such as subcutaneous, intramuscular and intravenous administration.
Tablets may for instance have the following composition:
THE INVENTION Both racemic (rac) and optically active (nat.) 4,6-dichloro-4,6-estraidenes of the above given formula (I) may be formed, for instance, as follows:
The starting product is a 6-chloro-4,6-estradiene of the formula wherein R is hydrogen, alkyl, tetrahydropyranyl or an acid residue. These compounds are subjected to the action of an agent furnishing positive and negative chlorine so as to form the 6,6,7-trichloro compound. The latter compound is then treated with a base. Depending on the desired character of R and the starting compound employed (in respect of R), an esterified or etherified hydroxyl group may then be subjected to hydrolysis or, if a free hydroxyl group is present, the latter group may be esterified or etherified.
Positive and negative chlorine may be obtained during the reaction from suitable chlorine-containing compounds. Positive chlorine for instance is obtained from N-chloroacylamides or -acylimides, preferably N-chloro-acetamide or N-chloro-succinimide. However, hypochlorites may also be used, such as tert. butylhypochlorite.
Agents furnishing negative chlorine are for instance chlorides, preferably lithium chloride.
In addition it is also possible to split up elementary chlorine into positive and negative chlorine.
For instance, a steroid of the formula given above for the starting compounds may be dissolved in acetic acid and then subjected to the action of lithium chloride and N-chlorosuccinimide in the presence of a strong anhydrous acid such as hydrochloric acid in dioxane or tetrahydrofuran. The corresponding 6,6,7-trichloro compound is then formed by chlorination of the A -double bond. The trichloro compound is thereafter treated, preferably with an organic base, to split off hydrogen chloride. The splitting off of the hydrogen chloride is accompanied by a migration of the chlorine atom to the 4-position.
Chlorination and hydrogen chloride elimination take place under mild conditions, preferably at temperatures around room temperature.
The subsequent esterification, etherification and saponification reactions can be carried out in conventional manner.
For instance, for the purpose of esterification, a reaction may be chosen with an acid anhydride or acid halide in the presence of an acidic or basic agent or the reaction may be carried out with the desired free acid in the presence of trifluoroacetic acid anhydride.
For the purpose of the saponification, it is preferable to subject the 17-carboxylic acid esters to the action of a base, for instance an alkali hydroxide, alcoholate or alkali carbonate in the presence of water, preferably an alcoholic solution and, if desired, upon addition of a solution promoting agent.
To make the 17-tetrahydropyranylethers, the 17-hydroxy compound can be reacted with dihydropyran in the presence of an acid such as p-toluenesulfonic acid. The etherification with an alkyl residue preferably is effected with an alkyl halide in the presence of a basic condensation agent such as silver oxide.
MAKING OF THE STARTING PRODUCTS The starting products of the above-given formula (II) may for instance be obtained as appears from the following two examples:
'-(A) Rac.-6-chloro-l7/3-acetoxy-l8-rnethy1- 17a-ethinyl-4,6-estradiene-3-one Rae. l7/3-acetoxy-18-methyl-17a-ethinyl 4 estrene-3- one is reacted with formic acid ethyl ester in the presence of concentrated sulfuric acid in dioxane at room temperature. The thus-obtained rac.-3-ethoxy-l7 8-acetoxy-l8- methyl-17a-ethinyl-3,5-estradiene, M.P. -183 C., is brominated with N-bromosuccinimide in the 6-position. Hydrogen bromide is then split oif from the resulting 6B-bromo-17,6-acetoxy-18-methyl-17a-ethinyl 4 estrene- 3-one in dimethylformamide in the presence of lithium bromide and lithium carbonate. There is thus obtained racemic 17,B-acetoxy 18 methyl-17ct-ethinyl-4,6-estradiene-3-one; M.P. 167.5-172 C.
In order to introduce the chlorine atom in the 6-position, the 6u,7a-epoxide is formed with m-chloroperbenzoic acid and the epoxide is then treated with hydrogen chloride in acetic acid at room temperature. The resulting rac.-6 8-chloro-7a-hydroxy-17B-acetoxy 18 methyl-17aethinyl-4-estrene-3-one is converted to the 7-mesylate with methane sulfonic acid chloride in pyridine. From the 7- mesylate the rac.-6-chloro-l7 8-acetoxy 18 methyl-17aethinyl-4,6-estradiene-3-one is obtained by heating in pyridine in the presence of sodium acetate; M.P. 203-205 C.
(B) Nat.-6-chloro-17 3-acetoxy-18 -methyl- 17a-ethinyl-4,6-estradiene-3-one Nat.-17/3-acetoxy 18 methyl-l7u-ethinyl-4-estrene-3- one is converted to the 3-enolethylether in the same manner as was used in Example A. By bromination and subsequent elimination of hydrogen chloride, there is obtained nat.-17fi-acetoxy-l8-methyl-l7u-ethinyl-4,6-estradiene-3-one; M.P. 206-207 C. (UV: e =26,100).
To introduce the chlorine atom in the 6-position, the 6u,7a-epoxide is formed with m-chloroperbenzoic acid.
1.4 g. of rac.-6-chloro-17B-acetoxy 18 methyl-17aethinyl-4,6-estradiene 3 one was dissolved in 200 ml.
acetic acid and successively reacted with 7 g. of lithium chloride, 1.4 g. of N-chlorosuccinimide and 0.3 ml. dioxane saturated with hydrogen chloride gas. After a reaction time of 7 minutes at room temperature, the product is added while stirring to ice water and the formed precipitate is removed then by suction and taken up in methylene chloride. The methylene chloride phase is washed with sodium bicarbonate solution and water, dried over sodium sulfate and concentrated by evaporation to dryness in a vacuum.
The residue is dissolved in 5 ml. pyridine and permitted to stand for 16 hours at room temperature. It is thereafter taken up in ether, washed with dilute hydrochloric acid and water, dried and concentrated by evaporation to dryness in a vacuum. The residue is subjected to chromatography on silica gel and thereafter recrystallized from acetone/hexane. There is obtained 0.6 g. of rac.-4,6- dichloro-17fl-acetoxy 18 methyl-l7a-ethinyl-4,6-estradiene-3-one; M.P. 210-213.5 C. (decomposition).
EXAMPLE 2 Nat.-6-chloro-17fi-acetoxy 18 methyl 17cc ethinyl- 4,6-estradiene-3-one is reacted analogously to Example 1 and subjected to the same further treatment. There is obtained nat.-4,6-dichlord17,6-acetoxy 18 methyl 17ozethinyl-4,6-estradiene-3-one; M.P. 230-231.5 C. UV: 3D3=18,100.
EXAMPLE 3 1.9 g. of nat.-6-chloro-17/3-hydroxy-18methyl-17a-ethinyl-4,6-estradiene-3-one are dissolved in 300 ml. acetic acid and successively reacted with 10 g. of lithium chloride, 1.9 g. of N-chlorosuccinimide and 0.4 ml. dioxane/ HCl. After a reaction time of 7 minutes at room temperature, the subsequent treatment is started and carried out as in Example 1.
The isolated product is then dissolved in 5 ml. pyridine and left standing for 16 hours at room temperature. It is then taken up in ether, washed with dilute hydrochloric acid and water, dried and concentrated by evaporation to dryness in a vacuum. The residue is subjected to chromatography on silica gel and, after recrystallization from acetone/hexane, 400 mg. of nat.-4,6-dichloro-17B-hydroxy-l8-methy1-17a-ethinyl-4,6-estradiene-3-one are obtained; M.P. 216-216.5 C. UV: e =16,800.
EXAMPLE 4 1.0 g. of nat.-6-chlor0-17 3-heptanoyloxy-18-methyl- 17wethinyl-4,6-estradiene-3-one are dissolved in 100 ml. acetic acid and reacted with 5.0 g. lithium chloride, 1 g. N- chlorosuccinimide and 0.2 ml. dioxane/HCl. After a reaction time of 7 minutes at room temperature, the following treatment is started and carried out as in Example 1. The product is subsequently treated with pyridine and then subjected to chromatography on silica gel. There are obtained 350 mg. of nat.-4,6-dichloro-17fi-heptanoyloxy- 18-methyl-17a-ethinyl-4,6-estradiene-3-one in the form of an oil. UV: e =17,000.
6 EXAMPLE 5 500 mg. of nat.-4,6-dichloro -17 S-acetoxy-18-methyl- 17u-ethinyl-4,6-estradiene-3-one are heated in 50 ml. methanol with 500 mg. p-toluenesulfonic acid for 24 hours while slowly effecting distillation. The mass is then diluted with ether, washed with water and concentrated by evaporation to dryness in a vacuum. After recrystallization from acetone/hexane there is obtained nat.-4,6-dichloro-17flhydroxy-18-methyl-17a-ethinyl-4,6-estradiene-3-one; M.P. 215-216" C. UV: e =16,500.
What is claimed is:
1. A racemic or optically active 4,6-dichloro-4,6-estradiene of the formula wherein R is hydrogen, lower alkyl, tetrahydropyranyl or a carboxylic acid group containing up to 15 carbon atoms.
2. The estradiene of claim 1, wherein alkyl is methyl, ethyl, propyl or butyl.
3. The estradiene of claim 1, wherein the acid residue is formed of a carboxylic acid having up to 15 carbon atoms.
4. The estradiene of claim 1, which is rac.-4,6-dichloro- 17,8-acetoxy-18-methyl-l7a-ethinyl-4,6-estradiene-3-one.
S. The estradiene of claim 1, which is nat.-4,6-dichloroacetoxy-l8-methyl-17a-ethinyl-4,6-estradiene-3-one.
6. The estradiene of claim 1, which is nat.-4,6-dichloro- 17,9 hydroxy-18-methyl-17a-ethinyl-4,6-estradiene-3-one.
7. The estradiene of claim 1, which is nat.-4,6-dichloro- 117,8 heptanoyloxy-lS-methyl-17u-ethinyl-4,6-estradiene- -one.
8. The process of making the compounds of claim 1 comprising subjecting a 6-ch1or0-4,6-estradiene of the formula wherein R has the meaning as given in claim 1, to the ac tion of an agent furnishing positive and negative chlorine, thereby forming the 6,6,7-trichloro compound and then treating the trichloro compound with a base.
9. The process of claim 8 wherein the 21-OR group is an ester or ether group in the starting product and wherein the final product is then subjected to hydrolysis of the said ester or ether group.
10. The process of claim 8 wherein the '21-OR group of the starting product is a free hydroxyl group and wherein the final product is subjected to esterification or etherification of the 21-hydroxyl group.
7 8 11. The process of claim 8, wherein as agent furnish- References Cited ing positive chlorine N-chlorosuccinimide or N-chloro- UNITED STATES PATENTS acetamide is employed.
12. The process of claim 8, wherein as negative ch1o- 3462464 8/1969 Hlrschman et 260*3974 rine furnishing agent lithium chloride is employed. 3513164 5/1970 Cross at 260 239'55 13. The process of claim 8, wherein the base is an or- HENRY A, FRENCH, Primary Ex iner ganic base.
14. The process of claim 13, wherein the base is pyridine. 260--239.55 R; 424-243
US00853480A 1968-09-13 1969-08-27 Dichloro-substituted estradiene Expired - Lifetime US3812166A (en)

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US20060115542A1 (en) * 2001-05-15 2006-06-01 Motterlini Roberto A Therapeutic delivery of carbon monoxide
US20060127501A1 (en) * 2002-11-20 2006-06-15 Motterlini Roberto A Therapeutic delivery of carbon monoxide to extracorporeal and isolated organs
US20060148900A1 (en) * 2002-02-04 2006-07-06 Alfama - Investigacao E Desenvolvimento De Produtos Farmaceuticos Lda Method for treating a mammal by administration of a compound having the ability to release CO, compounds having the ability to release CO and pharmaceutical compositions thereof
US20070219120A1 (en) * 2002-02-04 2007-09-20 Alfama - Investigacao E Desenvolvimento De Productos Farmaceuticos Lda Methods for treating inflammatory disease by administering aldehydes and derivatives thereof
US20080026984A1 (en) * 2002-02-04 2008-01-31 Alfama - Investigacao E Desenvolvimento De Productos Farmaceuticos Lda Methods for treating inflammatory disease by administering aldehydes and derivatives thereof
US8389572B2 (en) 2006-01-24 2013-03-05 Hemocorm Limited Therapeutic delivery of carbon monoxide
US9062089B2 (en) 2011-07-21 2015-06-23 Alfama, Inc. Ruthenium carbon monoxide releasing molecules and uses thereof
US9163044B2 (en) 2011-04-19 2015-10-20 Alfama, Inc. Carbon monoxide releasing molecules and uses thereof

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CH499505A (en) * 1966-02-23 1970-11-30 Hoffmann La Roche Steroids of the partial formula (I):- where R1 is halogen (at wt.100) or alkyl Q is oxo or 1,2-alkylenedioxy (2-4C) M is the remainder of the

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US8236339B2 (en) 2001-05-15 2012-08-07 Hemocorm Limited Therapeutic delivery of carbon monoxide
US20060115542A1 (en) * 2001-05-15 2006-06-01 Motterlini Roberto A Therapeutic delivery of carbon monoxide
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Also Published As

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ES370887A1 (en) 1971-07-01
NL164041B (en) 1980-06-16
CH536294A (en) 1973-04-30
NL6913959A (en) 1970-03-17
IL32973A0 (en) 1969-11-30
SE352080B (en) 1972-12-18
DE1793422A1 (en) 1971-07-01
FR2018070A1 (en) 1970-05-29
BR6912323D0 (en) 1973-03-13
BE738803A (en) 1970-03-12
NL164041C (en) 1980-11-17
DE1793422B2 (en) 1977-01-20
GB1287602A (en) 1972-09-06
IL32973A (en) 1974-07-31
DK121656B (en) 1971-11-15
AT289307B (en) 1971-04-13

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