US3149132A - 16-aminomethyl-17-alkyltestosterone derivatives - Google Patents
16-aminomethyl-17-alkyltestosterone derivatives Download PDFInfo
- Publication number
- US3149132A US3149132A US229747A US22974762A US3149132A US 3149132 A US3149132 A US 3149132A US 229747 A US229747 A US 229747A US 22974762 A US22974762 A US 22974762A US 3149132 A US3149132 A US 3149132A
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- Prior art keywords
- methyl
- derivatives
- ethyl
- aminomethyl
- alkyltestosterone
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0038—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 with an androstane skeleton, including 18- or 19-substituted derivatives, 18-nor derivatives and also derivatives where position 17-beta is substituted by a carbon atom not directly bonded to a further carbon atom and not being part of an amide group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
Definitions
- R and R are lower alkyl of from 1 to 6 carbon atoms inclusive or, when taken together with the nitrogen atom to which they are attached, a standard heterocyclic end group such as pyrrolidinyl, N-lower-alkyl-N-pipera- Zinyl, morpholinyl, piperidinyl, or thiomorpholinyl.
- nontoxic pharmaceutically acceptable acid addition and quaternary ammonium salts of the bases of Formula 1 such as salts formed with acids such as hydrochloric, sulfuric, acetic, phosphoric, maleic, ethanedisulfonic etc'. acids or quaternaries made with such standard quaternizing agents as methyl iodide, ethyl chloride, methyl sulfate, propyl bromide, ethyl bromide etc.
- These salts are prepared by standard methods such as reaction of the Mannich base in inert organic solvent such as ether with an excess of the acid or quaternizing agent.
- the compounds of this invention as described above have been unexpectedly found to have anti-anabolic or particularly, anti-androgenic activity. In other words these compounds when administered concurrently with testosterone antogonize the well known effects of that drug. Compounds having such activity are variously efieclli' against certain prostate conditions and to treat females exhibiting the Stein-Leventhal syndrome or hirsutism.
- the compounds of this invention are prepared using known Mannich derivatives of dehydroisoandrosterone (U.S. Patent No. 2,562,194, US. Patent No. 2,890,227 and US. Patent No. 2,588,341). It should be noted that the configuration of the l6-aminomethyl moiety of the starting material of these patents is described as a mixture of a and [3. While this is not disputed, the major portion of the mixture seems from our data to be a and the compounds described hereafter may be so considered. The configuraton at positions 16 and 17 does not seem to have any efi ect on the utility of the compounds.
- the Mannich starting materials are reacted with a Grignard agent such as methyl or ethyl magnesium bromide to produce the l6-aminornethyl-l7-methyl-5-androsten-3,17- diol which is in turn oxidized usually under Oppenauer conditions to the products of Formula 1.
- a Grignard agent such as methyl or ethyl magnesium bromide
- the Grignard reaction can also result in a mixture of isomers at 17. Both series are included in this invention. Separation of the isomers is detailed in Example 1 but both isomeric compounds have the desired utility.
- Example 1 210 ml. of a 3-molar ethereal solution of methyl magnesium bromide are added slowly to 210 ml. of tetrahydrofuran. The mixture is stirred and warmed to remove ether, the last traces under vacuo. A solution of 33.5 g. of l6-dimethylaminomethyl-5-androsten-3B-0l-17-one in 600 ml. of tetrahydrofuran is added. The mixture is stirred for several hours, then allowed to stand overnight. A solution of 67 g. of ammonium chloride in 300 ml. of water is cautiously added with stirring and cooling. The organic layer is separated, washed and evaporated to give a crystalline residue of the 17-methylated compound, M.P. 172-190 C.
- the isomeric mixture is separated by fractional crystallization from ethyl acetate to give less soluble plates of 16oz dimethylaminomethyl 17 oz methyl 5 androsten- 3B,l7;3-diol, M.P. 245-247 C., [ak z -84, and needles of 16m-dimethylaminomethyl-17B-rnethyl-5-androstem-35,17a-diol, M.P. 189-191 C., [ak z 41.
- the configuration at 17 is assigned by comparison of the infrared curves.
- the 17,8-l1ydroxy isomer (MP. 245 C., 6 g.) is oxidized to give crystals from ether of 16OL-dlI1lethYlaminomethyl-l7a-methyl-testosterone, M.P. 131-133" C., l lcnol
- the 1711-01 (500 mg.) in chloroform is saturated with dry hydrogen chloride gas to separate the hydrochloride salt.
- Another portion is reacted with ethyl iodide at reflux in chloroform to give the ethiodide quaternary salt.
- Example 2 16-Piperidinylmethyldehydroisoandrosterone (11 g.) is reacted with an excess of ethyl magnesium chloride in tetrahydrofuran as in Example 1 to give the isomeric 16 piperidinylmethyl 17 ethyl 5 androsten 35,17- diols which (8 g.) are oxidized with aluminum isopropoxide cyclohexanone to give the 16-piperidinylmethyl-17-ethyltestosterones.
- Example 3 Substituting 7.5 g. of 16-diethylaminomethyldehydroisoandrosterone in the sequence of Example 1 gives with methyl magnesium bromide in tetrahydrofuran first the separated isomeric l6-diethylan1inomethyl-17-methyl- 5-androsten-3[3,l7-diols and then the isomeric 16-diethylaminomethyl-l7-methyltestosterones.
- Example 1 Substituting equimolar amounts of l6u-N-methylpiperazinylrnethyldehydroisoandrosterone (prepared by the Julian method, US. Patent No. 2,562,194, using N-methylpiperazine, formaldehyde and dehydroisoandrosterone) in Example 1 gives l6u-N-methylpiperazinylmethyl-17-rnethyl-5-androsten-3fi,17-diol then Oppenauer oxidation gives 1-N-methylpiperazinylmethyl-17-methyltestosterone.
- R is a member selected from the group consisting of methyl and ethyl; and R and R are members selected from the group consisting of lower alkyl and, when taken together with the nitrogen to which they are 4 attached, piperidinyl, morpholinyl, pyrrolidinyl, N-lower alkyl-piperazinyl and thiornorpholinyl.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
United States Patent 3,149,132 16-AIt mJDPfiTHYL-17-ALKYLTESTOSTERGNE DERIVATIVES Percy 1.. Julian, Oak Park, and Arthur Magnani, Wilmette, Ill, assignors, by mesne assignments, to Smith Kline & French Laboratories, Philadelphia, Pa, a corporation of Pennsylvania No Drawing. Filed Oct. 10, 1962, Ser. No. 229,747 7 Claims. (Cl. 260-3914) This invention relates to novel Mannich derivatives of 17-alkyltestosterones which have unexpectedly been found to have novel pharmacodynamic activity.
More specifically the compounds of this invention are represented by the following formula:
R OH /R1 NWOH2N FORMULA 1 in which R is lower alkyl, preferably methyl or ethyl;
R and R are lower alkyl of from 1 to 6 carbon atoms inclusive or, when taken together with the nitrogen atom to which they are attached, a standard heterocyclic end group such as pyrrolidinyl, N-lower-alkyl-N-pipera- Zinyl, morpholinyl, piperidinyl, or thiomorpholinyl.
Also included in this invention are the nontoxic pharmaceutically acceptable acid addition and quaternary ammonium salts of the bases of Formula 1 such as salts formed with acids such as hydrochloric, sulfuric, acetic, phosphoric, maleic, ethanedisulfonic etc'. acids or quaternaries made with such standard quaternizing agents as methyl iodide, ethyl chloride, methyl sulfate, propyl bromide, ethyl bromide etc. These salts are prepared by standard methods such as reaction of the Mannich base in inert organic solvent such as ether with an excess of the acid or quaternizing agent.
The compounds of this invention as described above have been unexpectedly found to have anti-anabolic or particularly, anti-androgenic activity. In other words these compounds when administered concurrently with testosterone antogonize the well known effects of that drug. Compounds having such activity are variously efieclli' against certain prostate conditions and to treat females exhibiting the Stein-Leventhal syndrome or hirsutism.
The compounds of this invention are prepared using known Mannich derivatives of dehydroisoandrosterone (U.S. Patent No. 2,562,194, US. Patent No. 2,890,227 and US. Patent No. 2,588,341). It should be noted that the configuration of the l6-aminomethyl moiety of the starting material of these patents is described as a mixture of a and [3. While this is not disputed, the major portion of the mixture seems from our data to be a and the compounds described hereafter may be so considered. The configuraton at positions 16 and 17 does not seem to have any efi ect on the utility of the compounds. The Mannich starting materials are reacted with a Grignard agent such as methyl or ethyl magnesium bromide to produce the l6-aminornethyl-l7-methyl-5-androsten-3,17- diol which is in turn oxidized usually under Oppenauer conditions to the products of Formula 1.
The Grignard reaction can also result in a mixture of isomers at 17. Both series are included in this invention. Separation of the isomers is detailed in Example 1 but both isomeric compounds have the desired utility.
Patented Sept. 15, 1964 "ice It will be apparent to one skilled in the art that various well-known modifications of the steroids of Formula 1 can be made, however, the nub of this invention is considered to be the vital 16-arninomethyl moiety coupled with the basic 17-methyltestosterone nucleus. Standard Variations such as 19-nor, 4-halo, methyl or hydroxy, 6- halo or methyl, 11 or 12-hydroxy, A or other modifications can be made by methods known to the art and are within the purview of this invention. The term lower alkyl where used herein means straight or branched alkyl groups of l to 6 carbon atoms inclusive but preferably methyl or ethyl.
The following examples will illustrate the synthetic methods necessary for one skilled in the art to practice this invention.
Example 1 210 ml. of a 3-molar ethereal solution of methyl magnesium bromide are added slowly to 210 ml. of tetrahydrofuran. The mixture is stirred and warmed to remove ether, the last traces under vacuo. A solution of 33.5 g. of l6-dimethylaminomethyl-5-androsten-3B-0l-17-one in 600 ml. of tetrahydrofuran is added. The mixture is stirred for several hours, then allowed to stand overnight. A solution of 67 g. of ammonium chloride in 300 ml. of water is cautiously added with stirring and cooling. The organic layer is separated, washed and evaporated to give a crystalline residue of the 17-methylated compound, M.P. 172-190 C.
The isomeric mixture is separated by fractional crystallization from ethyl acetate to give less soluble plates of 16oz dimethylaminomethyl 17 oz methyl 5 androsten- 3B,l7;3-diol, M.P. 245-247 C., [ak z -84, and needles of 16m-dimethylaminomethyl-17B-rnethyl-5-androstem-35,17a-diol, M.P. 189-191 C., [ak z 41. The configuration at 17 is assigned by comparison of the infrared curves.
The 17a-hydroxy isomer (8 g.) in 500 ml. of toluene and 30 ml. of cyclohexanone at 100 C. with 4 g. of aluminum isopropoxide is heated at reflux for 45 minutes, allowed to cool to C. and diluted with 5 ml. of water. The separated filtrate is steam distilled. The residue is recrystallized from ethyl acetate to give lfia-dimethylaminomethyl-l7fi-methyl-4-androsten-17a-ol-3-one, MP.
Similarly the 17,8-l1ydroxy isomer (MP. 245 C., 6 g.) is oxidized to give crystals from ether of 16OL-dlI1lethYlaminomethyl-l7a-methyl-testosterone, M.P. 131-133" C., l lcnol The 1711-01 (500 mg.) in chloroform is saturated with dry hydrogen chloride gas to separate the hydrochloride salt. Another portion is reacted with ethyl iodide at reflux in chloroform to give the ethiodide quaternary salt.
Example 2 16-Piperidinylmethyldehydroisoandrosterone (11 g.) is reacted with an excess of ethyl magnesium chloride in tetrahydrofuran as in Example 1 to give the isomeric 16 piperidinylmethyl 17 ethyl 5 androsten 35,17- diols which (8 g.) are oxidized with aluminum isopropoxide cyclohexanone to give the 16-piperidinylmethyl-17-ethyltestosterones.
This material with sulfuric acid in chloroform gives the sulfate salt.
Example 3 Substituting 7.5 g. of 16-diethylaminomethyldehydroisoandrosterone in the sequence of Example 1 gives with methyl magnesium bromide in tetrahydrofuran first the separated isomeric l6-diethylan1inomethyl-17-methyl- 5-androsten-3[3,l7-diols and then the isomeric 16-diethylaminomethyl-l7-methyltestosterones.
' Substituting equimolar amounts of l6u-N-methylpiperazinylrnethyldehydroisoandrosterone (prepared by the Julian method, US. Patent No. 2,562,194, using N-methylpiperazine, formaldehyde and dehydroisoandrosterone) in Example 1 gives l6u-N-methylpiperazinylmethyl-17-rnethyl-5-androsten-3fi,17-diol then Oppenauer oxidation gives 1-N-methylpiperazinylmethyl-17-methyltestosterone. V Substituting 16-morpholinylmethyldehydroisoandrosterone, 16-pyrrolidinylmethyldehydroisoandrosterone or 16-methylaminornethyldehydroisoandrosterone in the process of Example 1 give respectively the 3-ol-5-enes and then the 16-morpholinylmethyl-17-methyltestosterone, 16 pyrrolidinylmethyl 17 methyltestosterones and 16- methylaminomethyl-l7-methyltestosterones.
What is claimed is: V
1. A compound selected from the group consistingof a free base, its nontoxic pharmaceutically acceptable acid addition salts and its nontoxic pharmaceutically acceptable quaternary ammonium salts, said free base having the formula:
in which R is a member selected from the group consisting of methyl and ethyl; and R and R are members selected from the group consisting of lower alkyl and, when taken together with the nitrogen to which they are 4 attached, piperidinyl, morpholinyl, pyrrolidinyl, N-lower alkyl-piperazinyl and thiornorpholinyl.
2. A compound of the formula:
CH3 OH 7 I nomm,
3. 16a dimethylaminomethyl 17,8 7 methyl 4-andro- 4.1Ga-dimethyIaminomethyl-17a-methyltestosterone.
5. A compound of the structure: 7 R 011 V /R1 20 MN CHzN I HO C v No references cited.
Claims (1)
1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF A FREE BASE, ITS NONTOXIC PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS AND ITS NONTOXIC PHARMACEUTICALLY ACCEPTABLE QUATERNARY AMMONIUM SALTS, SAID FREE BASE HAVING THE FORMULA:
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| BE638481D BE638481A (en) | 1962-10-10 | ||
| US229747A US3149132A (en) | 1962-10-10 | 1962-10-10 | 16-aminomethyl-17-alkyltestosterone derivatives |
| GB38037/63A GB1031080A (en) | 1962-10-10 | 1963-09-26 | Improvements in or relating to 16-aminomethyl-17-alkyl-testosterone and -isotestosterone derivatives |
| FR949770A FR3327M (en) | 1962-10-10 | 1963-10-07 | Medicinal product which can be used in particular as an anti-anabolic and anti-androgen based on 16-aminoethyl-17-alcoyltestosterone derivatives. |
| DEJ24527A DE1242606B (en) | 1962-10-10 | 1963-10-08 | Process for the preparation of 16-tert-aminomethyl-17-alkyltestosterones or acid addition salts or quaternary ammonium compounds thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US229747A US3149132A (en) | 1962-10-10 | 1962-10-10 | 16-aminomethyl-17-alkyltestosterone derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3149132A true US3149132A (en) | 1964-09-15 |
Family
ID=22862532
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US229747A Expired - Lifetime US3149132A (en) | 1962-10-10 | 1962-10-10 | 16-aminomethyl-17-alkyltestosterone derivatives |
Country Status (5)
| Country | Link |
|---|---|
| US (1) | US3149132A (en) |
| BE (1) | BE638481A (en) |
| DE (1) | DE1242606B (en) |
| FR (1) | FR3327M (en) |
| GB (1) | GB1031080A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3351590A (en) * | 1964-02-14 | 1967-11-07 | American Home Prod | 17-aminoalkyl ethers of 3-ketoestrenes |
-
0
- BE BE638481D patent/BE638481A/xx unknown
-
1962
- 1962-10-10 US US229747A patent/US3149132A/en not_active Expired - Lifetime
-
1963
- 1963-09-26 GB GB38037/63A patent/GB1031080A/en not_active Expired
- 1963-10-07 FR FR949770A patent/FR3327M/en active Active
- 1963-10-08 DE DEJ24527A patent/DE1242606B/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| None * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3351590A (en) * | 1964-02-14 | 1967-11-07 | American Home Prod | 17-aminoalkyl ethers of 3-ketoestrenes |
Also Published As
| Publication number | Publication date |
|---|---|
| GB1031080A (en) | 1966-05-25 |
| BE638481A (en) | |
| FR3327M (en) | 1965-05-24 |
| DE1242606B (en) | 1967-06-22 |
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