US2998423A - Esters of 19-nortestosterone - Google Patents

Esters of 19-nortestosterone Download PDF

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US2998423A
US2998423A US79035759A US2998423A US 2998423 A US2998423 A US 2998423A US 79035759 A US79035759 A US 79035759A US 2998423 A US2998423 A US 2998423A
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nortestosterone
effect
esters
anabolic
compounds
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Wit Erik Duyvene De
Overbeek Gerhard Anthony
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Organon NV
Organon Inc
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Organon NV
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J1/00Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J75/00Processes for the preparation of steroids in general

Description

United State Pa q o 2,998,423 ESTERS OF 19-NORTESTOSTERONE Erik 'Duyven De Wit, Oss, and Gerhard Anthony Overbeek, Nijmegen, Netherlands, assignors to Organon ice The compounds according to the invention are 17-esters of 1'9-nortestosterone and saturated and unsaturated ali phatic carboxylic acids having 9-4 8 carbon atoms.

These compounds can be prepared by converting hm West range,NJ a coulomb-on of New Jersey l9-nortestosterone into said esters in a manner known No brawing. Filed Fb. 2, 1959, Ser. No. 790,357 P so for ester a i n, for example y reacting Claims priority, application Netherlands Feb. 25, 1958 19-nortestosterone dissolved in a suitable solvent with the 4 Claims. (Cl. 260-4974) acid chloride of the desired acid or with the anhydride of said acid. V The present invention pertains to new esters of 19-n0r: 10 Th t ti f th fi t f compounds n th rel tion testosterone. between anabolic and androgenic activity is mostly car It is known that testosterone and esters thereof have an ied out b means f tests on castrated rats, i hi h. anabolic effect in addition 10 a andmganic effect some time after the administration of the compound to- Owing to their anabolic activity these compounds have be tested the weights of the musculus-levator ani andi been applied for example in the treatment of cancer of of h Seminal vesicles i determined, the breast, in which, however, the virilizing efiect is most At the same time the weights of these organs areundesirable. One hasv therefore long been seekingtor d ter ined of rats of the same age to which the com"- compounds that do have an anabolic but y a sllght pound in question has not been administered but which virilizing effect. have been treated further in quite the same manner. Esters of l9-nortestosterone are descrlbed, the ana- The difference in weight of the musculi levator ani li nd androgenic i y of which are y f (AMLA) then is a measure for the anabolic and thatof ably d- These arethe esters of l9-nortestostero ne the seminal vesicles (ASV) for the androgenic activity; and alipha'ilc cyclo-allphatlc-allphatlc ay a aclqs So the relation AMLA/ ASP is a measure for the rela- With 9 t0 Flght carbon atoms aromatlo'allp hatlo tion between anabolic and androgenic activity. g j t of whlch the ahphatlc Part contams 2 With substances which are destined for clinical apor car onaoms.

pl1cat1on it is desirablerthat th1s relation is as great as i i i esters f of '19 g z ig i possible. This relation should not only be favourable. at figgfgl b zzg ggi ig i g p g 55 g g a g a certain time after administration, but should maintain anabolic and androgenic activity is the most favouri faqourable value as long substance m able. Consequently this compound is applied in a very ex erts some S0 it may not be W t large number of cases, of which may be mentioned by after in ection the substance has a good anabohc effect way of example cancer of the breast, osteoporosis, and a Shght "mhzmg efiect, Whllo thls would be th V decubitus, retarded growth, asthenia, osteogenesis imother Way about after f 875511111916 a Weekperfecta and for which further reference may be made o above f 111 Whloh AMLA/ASV to the very extensive medical literature on this compound. mllled, rs v ry Suitable for testing anabolic compounds;

Although in most of the cases excellent results are obbficausa has pp that there is a very good'correlatained with this known compound, the need remains for 11011 between the effect 0f the substances in test and anabolically acting compounds having a more prolonged 40 on clinical application. I effect than the l9-nortestosterone fl-phenylpropionate I The present compounds have been tested according to (hereinafter indicated by nor-TPP). In addition one the above method and compared with the compound is searching for compounds in which the relation between S0 far known to be the compound having the most favour-1 the anabolic and the androgenic effect is even more able relation between anabolic and androgenic efrect, viz.- favourable than in the nor-TPP'. the nor-TPP. I 7

It is an object of this invention to provide new esters 1 The following results were obtained (each figure is of l9-nortestosterone the relation of the anabolic and the the result of an experiment performed with 8 rats weigh: androgenic effect of which is more favourable than in the mg about grams when the experiment started); nor-TPP and which have a duration of action which is The treatment consists of a single administration of substantially longer than that of the nor-TPP.. 50 1 mg. ofthe compound in question.

Effect after2 weeks Effect after 4 Weeks Effect after 6 weeks Treatment AMLA ABV AMLA/ AMLA ASV AMLA/ AMLA ASV AMLAI. Asv ASV ASV q nor-TPP 21.4 9.7 '22 5.3 5.4 7.0 7.1 19-n0rtest.unde- 4 cylenate 25. 4 5. 0 5. 3 as. e 5. 0 7. 7 a2. 1 5. 5 5. o IQ-nortest. octene carboxylate 21.2 5.9 4.5 35.2 5.4 5.7 24.3 4.8 5.1 19-nortest. dodecene earboxylate 22. 8 6. 0 3. 8 30. 3 5.1 5. 9 28. 6 3. 2 9.0 IQ-nortest. tetradecene carboxylate 22.5 4.5 4.9 22.4 4.2 5.3 20.1 3.7 5.4 19-nortest oleate 15. 8 3. 5 4. s 24. 2 4. 0 6. 0 25. 7 4. 1 s. a 19-nortest. decan ate 25.0 2. 7 9. 2 e2. 7 5. 5 11.4 50 5. s 7. a 19-nortest. laurate.-- 23. 2 2. 7 8. 6 5. s 12 5s 5. 9 s. 4 19-nortest. myria- 19. 4 2. 2 8. 8 42 4. 2 1o 43. 7 4.1 10. 7 19-nortest, palmt- It follows from this table that after 4 weeks the effect of the nor-TPP has ceased practically entirely.

As with this compound AMLA is only very slight after the said period of time, the statement of the value of AMLA/ASV has no purpose here (theoretically both ASV and AMLA would have to be nil if there is no efiect at all). It also appears from the table that the present compounds do not only have a larger proteinsaving effect but also a slighter androgenic effect, while even after 6 weeks a pronounced eifect is present.

That is the present compounds the relation between the anabolic and the androgenic effect would be so favourable could by no means be anticipated, because it is known that on esterification of testosterone with some of the acids in question the androgenic effect increases very strongly. It was not to be expected that with nor-testosterone the very anabolic effect and not the androgenic effect should be amplified to such a large extent.

The present compounds do not only have favourable efiects in the animal experiment, but also on clinical application. It has appeared for example in nitrogen balance experiments in men that in a certain case the protein-saving effect of the nor-TPP which is applied on a very large scale amounted to about g. daily during the first 15 days after injection, whereas this with for example the nortestosterone undecylenate and -decanoate amounted to about 25 g. daily after administration of an equal dose. This larger effect, added to the much more prolonged effect renders the present compounds very valuable for clinical application.

The initial effect of the 19-nortestosterone oleate and -palmitate is somewhat smaller than that of the other compounds; against this is the more prolonged efiect, as a result of which this compound becomes of great importance for veterinary application, because for example by a single injection in young pigs the protein formation can be promoted to a very great extent at the expense of the deposit of fat, as a result of which an improved meat is obtained in a shorter time. Any unpleasant taste of the meat, as is the case after injection of androgenic substances, need not be feared, because the androgenic effect of these compounds is negligible.

In addition to the acids with one double bond also acids with more than one double bond may be considered for the present process, as well as acids with a triple bond.

In the process according to the invention start is preferably made from the acid chloride of the acid in question.

The following examples illustrate the process.

Example I (a) 1 g. of 19-nortestosterone is dissolved in 3 ml. of dry pyridine, after which the resulting solution is cooled to 20 C. A solution of 1. g. of undecylenic acid chloride in 3 ml. of dry benzene is added to the cooled solution. The mixture is maintained at 15 C. for 16 hours and then poured into ice water. The aqueous liquid is extracted with benzene, the benzene solution is washed with respt. 1 N sodium hydroxide solution, 2 N hydrochloric acid and with water till neutral reaction.

Then the solution is dried on sodium sulphate, filtered, and evaporated to dryness. The residue, 1.63 g. is dissolved in hexane, this solution is filtered over 30 g. of neutral aluminium oxide, and evaporated to dryness. On paper chromatographic investigation it turned out that the obtained 19-nortestosterone l7-undecylenate which at room temperature is an oil consists of a single compound. [oz] =+39.6 (in chloroform). E 15,600 (in ethanol).

(b) In the same manner as mentioned sub (a) the octene carboxylic ester of 19-nortestosterone is prepared in a yield of 88%. E ,,=15,900 (in ethanol).

(0) In the same manner as mentioned sub (a) the dodecene carboxylic ester of 19-nortestosterone is prepared in a yield of 83%. E ,,=16,200 (in ethanol).

(d) In the same manner as mentioned sub (a) the tetradecene carboxylic ester of 19-nortestosterone is prepared in a yield of z39,.=15,600 (in ethanol).

(e) In the same manner as mentioned sub (a) the oleate of 19-nortestosterone is prepared in a yield of 87%. E ,,=l5,400 (in ethanol).

(7) In the same manner as mentioned sub (a) the clecanoate of 19-nortestosterone is prepared in a nearly quantitative yield. The ester is an oil at room temperature. E ,,=l6,000 (in ethanol).

(g) In the same manner as mentioned sub (a) the myristate of l9-nortestosterone is prepared in a yield of 95%. E 15,900 (in ethanol).

(h) In the same manner as mentioned sub (a) the palmitate of 19-nortestosterone is prepared in a yield of 90%. [a] =+32.9 (in chloroform), E ,,=l5,300 (in ethanol), M.P. 53-56 C.

Example ll 1 g. of l9-nortestosterone and 2 g. of lauric anhydride are dissolved in 20 ml. of dry pyridine. The mixture is refluxed for 4 hours. Then 2 ml. of water are added and refluxing is continued for some more hours in order to decompose the excess of anhydride. Then the mixture is evaporated to dryness, the residue is taken up in benzene, after which this benzene solution is treated in the manner of Example I. In this manner the 19-nortestosterone-17-laurate is obtained in a yield. [a] ==+37.4 (in chloroform); E ,,=l5,900; M.P. 45-46" C.

What we claim is:

1. l9-nortestosterone 17-esters of saturated straight chain aliphatic carboxylic acids containing from 10 to 14 carbon atoms.

2. l9-nortestosterone 17-decanoate.

3. 19-nortestosterone17-laurate.

4. -19-nortestosterone 17-myristate.

References Cited in the file of this patent UNITED STATES PATENTS 2,308,834 Ruzicka et a1. Jan. 19, 1943 2,756,244 Djerassi et a1. July 24, 1956 2,831,873 Pinson et a1 Apr. 22, 1958 2,868,809 Donia et a1. Jan. 13, 1959 2,904,562 Diczfalusy et al. Sept. 15, 1959 2,964,537 Engelfried et al. Dec. 13, 1960

Claims (1)

1. 19-NORTESTOSTERONE 17-ESTERS OF SATURATED STRAIGHT CHAIN ALIPHATIC CARNOXYLIC ACIDS CONTAINING FROM 10 TO 14 CARBON ATOMS.
US2998423A 1958-02-25 1959-02-02 Esters of 19-nortestosterone Expired - Lifetime US2998423A (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3506763A (en) * 1965-12-20 1970-04-14 Squibb & Sons Inc Method of promoting growth of animals with testololactones
US4083973A (en) * 1975-08-27 1978-04-11 Akzona Incorporated Pharmaceutical preparation adapted for oral administration
US5208032A (en) * 1988-07-15 1993-05-04 Rutgers, The State University Of New Jersey Increasing the growth of turkeys using implant of 19-nortestosterone
US20040058898A1 (en) * 2002-09-25 2004-03-25 Chang-Eun Jung Pharmaceutical composition for alleviating the violence of a mammal comprising nortestosterone derivatives

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2308834A (en) * 1936-06-15 1943-01-19 Ciba Pharm Prod Inc Polynuclear cyclic oxyketones and derivatives thereof and process of making same
US2756244A (en) * 1953-07-11 1956-07-24 Syntex Sa 19-norandrostanolones and process
US2831873A (en) * 1954-10-13 1958-04-22 Pfizer & Co C Testosterone 4, 4-dimethyl pentanoate
US2868809A (en) * 1954-08-12 1959-01-13 Upjohn Co 19-nortestosterone phenyl alkanoates
US2904562A (en) * 1958-01-20 1959-09-15 Leo Ab Esters of testosterone and 19-nortestosterone and method for the production thereof
US2964537A (en) * 1956-06-16 1960-12-13 Schering Ag Therapeutically valuable carboxylic acid esters of 17-alkyl-19-nor-testosterone

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2308834A (en) * 1936-06-15 1943-01-19 Ciba Pharm Prod Inc Polynuclear cyclic oxyketones and derivatives thereof and process of making same
US2756244A (en) * 1953-07-11 1956-07-24 Syntex Sa 19-norandrostanolones and process
US2868809A (en) * 1954-08-12 1959-01-13 Upjohn Co 19-nortestosterone phenyl alkanoates
US2831873A (en) * 1954-10-13 1958-04-22 Pfizer & Co C Testosterone 4, 4-dimethyl pentanoate
US2964537A (en) * 1956-06-16 1960-12-13 Schering Ag Therapeutically valuable carboxylic acid esters of 17-alkyl-19-nor-testosterone
US2904562A (en) * 1958-01-20 1959-09-15 Leo Ab Esters of testosterone and 19-nortestosterone and method for the production thereof

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3506763A (en) * 1965-12-20 1970-04-14 Squibb & Sons Inc Method of promoting growth of animals with testololactones
US4083973A (en) * 1975-08-27 1978-04-11 Akzona Incorporated Pharmaceutical preparation adapted for oral administration
US5208032A (en) * 1988-07-15 1993-05-04 Rutgers, The State University Of New Jersey Increasing the growth of turkeys using implant of 19-nortestosterone
US20040058898A1 (en) * 2002-09-25 2004-03-25 Chang-Eun Jung Pharmaceutical composition for alleviating the violence of a mammal comprising nortestosterone derivatives

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