|Publication number||US2878157 A|
|Publication date||Mar 17, 1959|
|Filing date||Feb 29, 1956|
|Priority date||Feb 29, 1956|
|Publication number||US 2878157 A, US 2878157A, US-A-2878157, US2878157 A, US2878157A|
|Inventors||Barry M Bloom, Gerald D Laubach|
|Original Assignee||Pfizer & Co C|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (13), Referenced by (3), Classifications (17)|
|External Links: USPTO, USPTO Assignment, Espacenet|
United States PatentO SULFUR CONTAINING STEROID COMPOSITIONS Barry M. Bloom and Gerald D. Laubach, Jackson Heights,
N. Y., assignors to Chas. Pfizer & Co., Inc., Brooklyn,
N. Y., a corporation of Delaware No Drawing. Application February 29, 1956 Serial No. 568,451 7 Claims. (Cl. 167-52) This invention is concerned with certain novel sulfur containing stereoid compounds which are hormonally inactive and are central nervous system depressants. These materials are pregnane derivatives which contain a sulfur atom attached at either the 3 or the 21 position of the nucleus. These materials also contain ionic ester groups at the 3 and/ or the 21 positions and are especially useful as anesthetic agents, and as intermediates in organic synthesis. 7
The valuable compounds of this invention are generically represented by the following structural formula CH2-E The stereochemical relationship of the hydrogen at C is not indicated since the compounds of this invention belong to both the normaland allo-serie's. This formula is intended to be generic to both series. Similarly the group D when monovalent is situated in either the a or the B configuration. The valuable products of this invention are related to the series of water soluble esters of pregnanolones patented by G. D. Laubach (U. S. Patent No. 2,708,651, granted May '17, 1955), but they contain a nuclearly attached sulfur atom at the 3 or the 21 position.
They are related in the same way to the ionic esters disclosed and claimed in copending application Serial No. 568,450 filed herewith. These compounds have certain advantages over their oxygen analogs in that they have improved phlebitic and other pharmaceutical properties which makes them particularly desirable for administration as central nervous system depressants.
D and/or E may be selected from a variety of organic units and may be ionic ester groups having one of the following formulas wherein L is chosen from the group consisting of an.
alkylene radical, a hydroxy-alkylene radical, the lower hydrocarbon ethers thereof, the lower hydrocarbon carboxylic acid esters thereof, a mercaptoalkylene radical, the lower hydrocarbon sulfides thereof, the lower hydrocarbon carboxylic acid thioesters thereof, an amino- 2,878,157 Patented Mar. 17, 1959 hydrocarbon'group is an aliphatic, cycloaliphatic, aromatic or araliphatic group and a hydrocarbon acid is the corresponding carboxylic acid. The L group may also be an hydrogen atoms or lower hydrocarbon groups having up .to about six carbon. atoms in each'group. At least one of said substitutents is a hydrogen atoms in each case. The following illustrate some of the various formulas for Y+.
M+ is a cation selected from the group consisting of sodium, potassium and ammonium of the types just described for Y+. Z is a pharmacologically acceptable anion. This term has a definite meaning to those skilled in the art. By this is meant an anion of an acid which can be used in physiological preparations to neutralize a basic medicinal agent. Such materials may be toxic at certain dosage-levels but at the concentrations required with the benzoic, toluie and phenylacetic acids. In other words a.
neutralized medicinal agent, toxic effects due to the anion are absent. Examples of such anions are chloride, bromide, sulfate, methosulfate, phosphate, tartrate, gluconate, citrate, succinate, maleate, etc.
.,Further structures from which D and E may be selected include the hydroxyl group, and lower hydrocarbon carboxylic acid esters thereof containing up to about eight carbon atoms in the added unit, a hydrogen atom, and a mercapto group. The mercapto group may be further substituted with a lower hydrocarbon or hydrocarbon carboxylic acid group containing up to about eight carbon atoms to form a sulfide or thiol ester function. D alone may also be a keto group. In the foregoing discussion, the alkylene radical referred to is an aliphatic alkyl. group containing two unoccupied valences which are available for attachment as shown for L in the structural formulas. This group may be straight or branched but it is so constituted that its principal chain, that is the chain between the two unoccupied valences, containsup to about six carbon atoms. The hydroxyalkylene, mercaptoalkylene, and aminoalkylene radicals are similarly constituted, but they contain a hydroxyl group, a mercapto group or an amino group attached to the alkylene group either .at one of the carbon atoms of the principal chain or to a carbon atom, of one of the branches if the alkylene group is branched. The hydroxyl,vmercapto or amino groups so attached may be further substituted by a lower hydrocarbon group or a lower hydrocarbon carboxylic acidv group as already described. The following formulas will further illustrate thetype of structure of the alkylene, hydroxyalkylene, substituted hydroxyalkylene, mercaptoalkylene, substituted mercaptoalkylene, aminoalkylene, andxsubstituted amino alkylene .groups.
It will be noted'that again these groups may be straight and However, it is preferred that said heterogroups be attached only to saturated carbon atoms. That is they appear within the principal chain of the L group and not at either end. More than one carbon atom is sometimes replaced by a heterogroup of the above types, but as a practical matter the compounds containing only one heterogroup in the L group are more readily synthesized and are therefore preferred.
The foregoing discussion of the structures of the D and E groups in the generic formula can be summarized as follows.
D is selected from the group consisting of (a) ionic ester groups of the formula:
and -S-S and wherein said heterogroups are attached to saturated carbon atoms and said L group contains up to about six atoms in its principal chain; M+ is a cation selected from the group consisting of sodium, potassium and NR+, each R represents a member of the group consisting of a hydrogen atom, and a lower hydrocarbon group containing up to about six carbon atoms; Z is a pharmacologically acceptable anion; (b) hydroxyl, and the lower hydrocarbon carboxylic acid esters thereof containing up to about eight carbon atoms in the added unit; (6) keto; (d) mercapto, lower hydrocarbon sulfides, and hydrocarbon carboxylic acid thioesters thereof having up to about eight carbon atoms in the added unit.
E is selected from the group consisting of (a) ionic ester groups as defined above; (b) hydroxyl, and lower hydrocarbon carboxylic acid esters thereof containing up to about eight carbon atoms in the added unit; (c) hydrogen; (d) mercapto, lower hydrocarbon sulfides, and lower hydrocarbon carboxylic acid esters thereof com taining up to about eight carbon atoms in the added unit; and with atleast one of D and E being an ionic ester group as defined above andone of'D and E containing nuclearly attached sulfur.
To further illustrate the structures of the valuable sulfur containing steroids of this invention, a few typical formulas are given-below.
e e i n v(CzHOaNHO l CH2) CHzCS- A CHzOCOCHnCHzC OzNB Pregnane-3,20rdione-2l-thiol and allo-pregnane-ZO-one- 2l-ol-3a-thiol are particularly useful intermediates in the synthesis of the valuable water soluble sulfur containing steroid ionic esters of this invention. The latter material is also useful as an intermediate in the preparation of similar 3-desoxyionic esters in the pregnane series since the sulfur at the 3 position can be removed by treatment with Raney nickel. The 3-desoxyionic esters are described in copending U. S. application Serial No. 508,803, filed May, 1955 (now U. S. Patent 2,820,737 issued January 21, 1958. These two intermediates themselves have been found to be central nervous system depressants. The former material was readily prepared from pregnane 3,20'di0fl6r20'01 by first preparing the ptoluenesulfonic acid ester of the 21 hydroxyl group and then treating this with potassium iodide and potassium thioacetate according to a known procedure for preparing thioacetate esters. The acetyl group was then removed by hydrolysis yielding the 2l-mercapto compound. This is illustrated by Equation 1.
GQGHzOSGsGuHgCHs-D OHBSH The starting material, pregnane-3,20-dione-2l-ol was obtained by the catalytic hydrogenation of desoxycorticosterone. The details of this process are described in copending application, Serial No. 484,561, filed January 27, 1955, and now abandoned.
Allo-pregnane-20-one-21-ol-3a-thiol is prepared by a similar sequence of reactions starting with allo-pregnane- 20-one-3;9,21-diol-21-acetate. Conversion of the free hydroxyl group to the p-toluenesulfonate ester, followed by treatment with potassium thioacetate, as described above, yielded the 3u-thioacetate. This thioacetate was desulfurized by treatment with Raney nickel providing the 3-desoxy intermediate for preparing the 3- desoxyionic esters referred to above. Hydrolysis of the diester yielded the desired mercapto compound. This process is illustrated in Equation 2.
C'HzOC 0 CH1 CO CH9 1J-C aCoH4S02O I l COCHzO COCHB CH:
01130 os- I ([JHzOH CO CH3 ;These two intermediates were then readily converted to a variety of the valuable anesthetic agents of this invention by the application of processes of U. S.
2,708,651, issued to G. D. Laubach, May 17, 1955, and
of copending application Serial No. 568,450 filed herewith. For example, succinoylation of the 3 and 21 mercapto or hydroxyl groups of the above materials yielded the hemisuccinate esters or thioesters. The
a sodium, potassium, ammonium and substituted ammonium salts of these hemisuccinates are water soluble and possess the unique property of depressing the central nervous system when administered to an animal. Salts containing these particular cations are preferred since they are, in addition, well tolerated by the animal body.
Preparation of these materials is shown in Equations 3 and 4.
C O CHaSH CH3 C O CHQSC CHrCHaC 0211 CH:
CII'HzOH CO I CH:
(EH20 if CH2OH2CO2H C 0 CH3 u HOzCCHzCHaCS These succinoylations were carried out by treatment of the pregnane derivatives in pyridine with an excess of succinic anhydride.
Treatment of the above mercapto steroids with chloroacetyl chloride yielded the chlorothioacetate ester which was also useful as an intermediate in the preparation of other water soluble ionic esters containing sulfur at the 3 or the 21 positions. This material contains a reactive halogen atom that is readily replaced by reaction with amines, alcohols, amino acids, etc. Use of difunctional amines and alcohols yielded products containing groups which were used to prepare salts which confer water solubility on the molecule. Useful hydrophilic groups of this type include the acid addition salts of esters containing amino functions and certain metal salts and the amine salts of those containing acidic functions. These materials likewise have proven to be useful as intravenous anesthetic agents. Two examples of such preparations are illustrated in Equation 5.
H C 011230 CH:N(CHJ)2.HCI CH3 course, be employed. The above steroid half-acid esters are also useful for the preparation of water soluble amides and carbohydrate esters which are useful as central nervous system depressants. Adaptations of processes described in copending U. S. application, Serial No. 549,514, filed November 28, 1955, relating to the preparation of such compounds in the pregnane series can be readily devised for use with the valuable sulfur containing half-acid ester intermediates of this invention.
A convenient alternative route to the preparation of the types of compounds illustrated by Equation involves, for example, treatment of the p-toluenesulfonate esters of Equations 1 and 2 with u-chloropotassium thioacetate rather than potassium thioacetate. This yields the same a-chloroacetyl ester which was obtained in Equation 5, and similarly the B-substituted compound. Syntheses of this type are illustrated by Equations 6 and 7.
CH: CHzOSOsCeHrGHs-p ii CHzSCCHzCl CH: l
ll CHzSC 011,01
our 4) V 3 Various modifications of the above methods may, of
O CHaOi JCHs 1? CHaOCCHI GO It is apparent that many types of syntheses may be used to prepare the valuable compounds of this invention. Many additional methods will occur to those skilled in the art. The distinguishing structural feature of the valuable water soluble anesthetic agents of this invention, however, is that they contain a nuclearly attached sulfur atom at the 3 or the 21 position of the pregnane nucleus. This sulfur atom is sometimes esterified by a water soluble ionic ester group as described above or it is unsubstituted and the water soluble ionic ester group appears at another position in the molecule. The sulfur atom is also sometimes substituted by other organic groups to form, for example, sulfides or thioesters.
The valuable sulfur containing water soluble ionic ester anesthetic agents of this invention were tested in mice by administering them intravenously in sterile aqueous solutions. Varying dosage levels were used with diiferent groups of mice. From this type of an experiment it was possible to determine at once the approximate toxicity andanesthetic activity of these compounds. For example, dosages of 15, 30, 60, 120 and 240 mg./kg. were administered to different groups of mice in sterile aqueous solutions. The groups of mice receiving dosages exceeding the toxic limit died. At the lower dosage levels anesthesia resulted. Those that received doses below the anesthetic level were substantially without symptoms. The anesthetic activity was determined by noting the sleeping time of the mice and by the duration of the loss of righting reflex experienced. Based on the data obtained in this manner with mice, the materials were administered first to dogs and then to monkeys at dosages calculated to give the anesthetic effect without harm to the animals. Confirmation of the results obtained in the mouse test was obtained although there were, of course, some species differences. in sensitivity. These compounds were found to be similarly active in human beings.
The preferred use of the valuable central nervous system depressants of this invention is in anesthesia. They are particularly well suited for use as pre or basal anesthetics in conjunction with inhalation anesthetics such as nitrous oxide, cyclopropane, and diethyl ether. For this type ofuse intravenous administration is preferred since the eifect of the drug generally takes place promptly when administered in this fashion. This is necessary so that the anesthetist will have close control of the degree of central nervous system depression of the patient. The
salts of these materials, that is the acid addition, the metal and the amine salts are water soluble and therefore well suited for this purpose since water and water containing small proportions of certain organic solvents such as glycerol or propylene glycol are about the only solvents that can be employed in human intravenous therapy. These materials can be prepared for use as sterile solid compositions by blending them with various excipients and carriers and then sterilizing the solid mixture for example with ethylene oxide, or they can be used alone without solid diluents when sterilized in such a fashion. The sterile solid is then dissolved in sterile water prior to use. Alternatively, the unsterilized solid composition or compound can be dissolved in water and the resulting solution sterilized by filtration through a bacteriological filter prior to use. These compounds may be employed in aqueous solutions containing other solutes for example enough saline or glucose to make them isotonic. They may be also administered by other routes such as orally, subcutaneously and intramuscularly. For this purpose, it is useful to compound them into tablets with various tablet forming material such as'starch or to prepare elixirs or suspensions with suitable carriers.
The following examples aregiven to further illustrate the methods for synthesizing the valuable products of this invention. However, it is to be understood that these are given for illustrative purposes only and are not to 'be construed as limiting the invention in any way.
EXAMPLE I Pregnane-3 ,20-di0ne -21 -thiol xggssz, 5.89, 8.85 1 This mixture of the 21-chloroand 21-p-toluenesul-.-
fonyl compounds was treated-with an equal weight of potassium iodide in acetone and refiuxedunder nitrogen for one'hour. The reaction mixture was cooled and the insoluble salts filtered. Freshly prepared sodium thioacetate was addedto the filtrate and the whole refluxed under nitrogen for 30 minutes. Concentration of the solvent aflforded a yellow crystalline residuewhich was taken up in ether-benzene and washed with water, dried over sodium sulfate and concentrated again, Trituration of the residue with ether gave tan prisms of pregnanc- 3,20-dione-21-th iol acetate, 142-1462.
Saponification of this material with methanolicpotassium carbonate afforded the thiol whose infrared spectrum confirmed its structure to be .pregnane-3,20;dione- ZI-thiol. 5
' EXAMPLE II PregnarIe ZZO-diUne-ZI-thi0l hemisuccinate I The mercapto pregnane derivative of Example I, 14.7 g., was dissolved in ml. of dry pyridine and treated with 14 g. of succinic anhydride. The solution was allowed to stand at room temperature overnight and then it was slowly poured into 1.5 liters of. water. The excess pyridine was neutralized with 3N hydrochloric acid and the solution diluted with 2 l. of water. The product precipitated as a white cystalline solid which was cooled, washed with water and dried in vacuo at 50 C.
EXAMPLE III- Pregnane-3,20-dione-21-thiol sodium hemisuccinate The sodium salt of the hemisuccinate ester of Example II was prepared by dissolving 1 g. of the ester in an equivalent quantity of 5% sodium bicarbonate solution. It was necessary to warm the solution before all of the material dissolved. A clear solution then resulted which was filtered through a bacteriological filter to sterilize it and the clear filtrate frozen, and dried from the'frozen state. The residue remaining was a fluffy, white crystalline solid which was the sodium salt of pregnane-3,20-dione- 21-thiol hemisuccinate in a suitable'condition for intravenous injection whendissolved in sterile water. A sample of this material was characterized by titration.
EXAMPLE IV Allo-pregnane-ZO-one-Z]-ol-3a-thiol Allo-pregnane-ZO-one-Bfl, 2l -diol 21-acetate, 5.05 g., and 4.75 g. of p-toluenesulfonyl chloride were slurried with 25 ml. of pyridine at roomtemperature protected from atmospheric moisture. The mixture was stored in this fashion for one dayand then the contents diluted with 150 ml. of 3 N hydrochloric acid with stirring and cooling. The resulting precipitate of the 3-p-toluenesulfonate ester was collected and washed thoroughly with water. The mixture was dried'in vacuo over phosphorus pentoxide yielding 8.3 g. of a colorless powder which was recrystallized from benzene and hexane to yield the purified 3-p-toluenesulfonate ester, M. P. 179-180 C.
REE; 5.72, 5.82, 6.26, 8.11
This p-toluenesulfonate ester was then refluxed for one hour with a 10% excess of potassium thioaceta'te dissolved in thioacetic acid. The solvent was evaporated and the residue triturated with water to yield allo-pregnane-20-one-2l-ol-Qa-thiol diacetate.
The diacetate was refluxed with methanolic potassium carbonate to yield the corresponding thiol alcohol which was recovered by pouring the mixture into water, cooling the product and washing it with water. It was dried in vacuo over phosphorus pentoxide. This material, allo-pregnane-20-one-2l-ol-Sa-thiol, was of suitable purity for further conversion to the valuable ionic esters of this invention.
' 11 EXAMPLE v 'Alla-pregndne-ZO-one-ZI -l-3a-thiol 3,21 dihemisuccinate The B-mercapto compound of Example IV, 14.7 g., was converted to the dihemisuccinate ester by treatment with 'succinic anhydride as described in Example II. This material was further converted to the disodium salt by the procedure of Example III to yield a sterile crystalline material suitable for the preparation of intravenously injectable solutions of the anesthetic agent.
' EXAMPLE VI Pregn ar zed,ZO-dione-ZI-th'iol ZI-cklofbacetate vHregnane3,20-dionee21-thiol of Example I, 17.4 g., was dissolved in pyridine and the solution cooled in an ice bath. The cooled solution was then treated with 0.1 mole of chloroacetyl chloride. After the reaction had subsided the mixture was allowed to stand at room temperature overnight and the 2l-ehloroacetate ester isolated by pouring the pyridine solution slowly into five volumes of ice water. The precipitate product was collected, washed with water and dried in vacuo. The chloroacetate ester produced by this procedure was of'suitable quality for conversion to various of the valuable ionic esters of this invention by replacement of the chlorine atom.
EXAMPLE vn Pregnane-3,20-dione-2l-thi0l-21-dimeihylaminoacetate hydrochloride The chloroacetate ester of Example VI, g., was dissolved in dimethyl formamide and treated with gaseous dimethylamine from a cylinder until the gain in weight of the solution corresponded to slightly more than an equivalent quantity of dimethylamine. The product was then precipitated by treatment of the dimethylformamide solution with twice its volumes of hexane. The composition of the product was confirmed by, determination of the ionic chlorine content by titration with standard silver nitrate solution.
' EXAMPLE VIII Pregrwne-3,20-di0ne-21 -thiol diethylaminoacetate hydrochloride Two grams of the chloroacetate of Example VI was dissolved in 20 ml. of pyridine and treated with 1 m1. of diethylarnine. The mixture was kept for 16 hours in a water bath at 60 C. and the product isolated by pouring the solution into 50 ml. of cold water. The solution was neutralized with sodium bicarbonate and the diethylaminoacetatefree base was recovered by extraction with methylene chloride. Evaporation of the solvent left an oil which was dissolved in hexane and treated with anhydrous hydrogen chloride from a cylinder. The hydrochloride salt precipitated and was recovered, washed with fresh solvent and dried. Its neutral equivalent determined by in an aqueous system with sodium hydroxide and in a non-aqueous system with perchloric acid agreed with the calculated value.
What is claimed is; g
1. .A compound having the formula CO OH: l
wherein L is chosen from the group consisting of-an alkylene radical, a hydroxyalkylene radical, the lower hydrocarbon ethers thereof, the lower hydrocarbon acid amides thereof, an azalkylene radical, an oxalkylene radical and a thialkylene radical wherein the heterogroups of said radicals are selected from the group consisting of O, -S,
and -S-S and wherein said heterogroups are attached to saturated carbon atoms and said L group 'contains up to about six atoms in its principal chain; M+ is a cation selected from the group consisting of sodium, potassium and NR+, each R represents a member of the group consisting of a hydrogen atom, and a lower hydrocarbon group containing up to about six carbon atoms; Z is a pharmacologically acceptable anion; (b) hydroxyl, and the lower hydrocarbon carboxylic acid esters thereof containing up to about eight carbon atoms in the added unit; (c) keto; (d) mercapto, lower hydrocarbon sulfides, and hydrocarbon carboxylic acid thioesters thereof having up to about eight carbon atoms in the added unit; E is selected from the group consisting of (a) ionic ester groups as defined above; (b) hydroxyl, and lower hydrocarbon carboxylic acid esters thereof containing up to about eight carbon atoms in the added unit; (0) hydrogen; (d) mercapto, lower hydrocarbon sulfides, and lower hydrocarbon carboxylic acid esters thereof containing up to about eight carbon atoms in the added unit; and with at least one of D and E being an ionic ester group as defined above and one of D and E containing nuclearly attached sulfur.
2. A pharmaceutical composition which comprises a compound as claimed in claim 1 together with a pharmaceutically acceptable carrier.
3. An anesthetic agent comprising a sterile aqueous solution of a compound as claimed in claim 1.
5. Pregnane-3,20-dione-2l-thiol sodium hemisuccinate.
6. Allo-pregnane-3,20-dione-21-thiol sodium hemisuccinate.
7. Pregnane-3,20-dione 21 thiol diethylaminoacetate hydrochloride.
References Cited in the file of this patent UNITED STATES PATENTS 2,304,836 Marker Dec. 15, 1942 2,429,171 Ruzicka Oct. 14, 1947 2,582,918 Bernstein et a1. Jan. 15, 1952 2,623,054 Levin et al. Dec. 23, 1952 2,693,476 Cummings et al Nov. 2, 1954 2,693,484 Cummings et a1. Nov. 2, 1954 2,697,108 Rosenkranz et al Dec. 14, 1954 2,708,651 Laubach May 17, 1955 2,744,109 Ralls May 1, 1956 2,814,632 Nussbaum Nov. 26, 1957 FOREIGN PATENTS 476,023 Canada Aug. 14, 1951 476,135 Canada Aug. 14, 1951 Great Britain Oct. 31, 1951 OTHER REFERENCES Djerassi et al.: J. Am. Chem. Soc., vol. 75: 3702 (1953).
|Cited Patent||Filing date||Publication date||Applicant||Title|
|US2304836 *||Aug 2, 1940||Dec 15, 1942||Parke Davis & Co||Method for the preparation of hydroxy steroid derivatives|
|US2429171 *||Apr 28, 1944||Oct 14, 1947||Ciba Pharm Prod Inc||Betaine derivatives and process of making same|
|US2582918 *||Dec 8, 1949||Jan 15, 1952||American Cyanamid Co||Dehydroisoandrosteryl mercaptan and process|
|US2623054 *||Oct 2, 1947||Dec 23, 1952||Upjohn Co||Steroid aldehydes|
|US2693476 *||Apr 7, 1951||Nov 2, 1954||Pittsburgh Plate Glass Co||Beta-carbonyl carboxylic acid esters of steroids|
|US2693484 *||Apr 7, 1951||Nov 2, 1954||Pittsburgh Plate Glass Co||Noncatalytic ester exchange reaction of beta-keto carboxylic acid esters|
|US2697108 *||Jan 18, 1951||Dec 14, 1954||Syntex Sa||16-thiobenzyl pregnenes and process|
|US2708651 *||Jan 7, 1955||May 17, 1955||Pfizer & Co C||Water-soluble esters of pregnanolones|
|US2744109 *||Jan 13, 1955||May 1, 1956||Searle & Co||3-ethylene mercaptoles of 21-hydroxy-4-pregnene-3, 20-dione, its 17-hydroxy derivative and esters thereof|
|US2814632 *||Feb 21, 1957||Nov 26, 1957||Schering Corp||Steroid compounds and methods for their manufacture|
|CA476023A *||Aug 14, 1951||American Cyanamid Company||Steroid mercaptan, esters thereof and methods of preparing the same|
|CA476135A *||Aug 14, 1951||Sterling Drug Inc.||Lower alkylmercaptoalkanoates of hormones|
|GB660199A *||Title not available|
|Citing Patent||Filing date||Publication date||Applicant||Title|
|US3028400 *||Mar 17, 1960||Apr 3, 1962||Nsw steroid thioethers and process|
|US5281587 *||Oct 18, 1991||Jan 25, 1994||Imperial College Of Science, Technology And Medicine||Steroid sulphatase inhibitors|
|US5344827 *||Oct 26, 1993||Sep 6, 1994||Imperial College Of Science, Technology And Medicine||Steroid sulphatas inhibitors|
|U.S. Classification||514/169, 514/177, 514/176, 552/557, 514/172, 552/609, 540/111, 552/600|
|International Classification||C07J75/00, C07J31/00, C07J5/00|
|Cooperative Classification||C07J31/00, C07J75/00, C07J5/00|
|European Classification||C07J5/00, C07J75/00, C07J31/00|