CA1315787C - Morpholine compounds and methods of use - Google Patents
Morpholine compounds and methods of useInfo
- Publication number
- CA1315787C CA1315787C CA000569596A CA569596A CA1315787C CA 1315787 C CA1315787 C CA 1315787C CA 000569596 A CA000569596 A CA 000569596A CA 569596 A CA569596 A CA 569596A CA 1315787 C CA1315787 C CA 1315787C
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- compound
- carbon atoms
- hydrogen
- alkyl
- composition
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Abstract
MORPHOLINE COMPOUNDS AND METHOD OF USE
ABSTRACT OF THE DISCLOSURE
There are disclosed compounds of the formula wherein R1, R2, R3, R4 and R5, which can be the same or different, are each selected from hydrogen, alkyl of 1 to 4 carbon atoms and alkoxy of 1 to 4 carbon atoms; and R6 and R7, which can be the same or different, are each selected from hydrogen and alkyl 1 to 3 carbon atoms.
The compounds are useful as growth promoting agents in animals.
ABSTRACT OF THE DISCLOSURE
There are disclosed compounds of the formula wherein R1, R2, R3, R4 and R5, which can be the same or different, are each selected from hydrogen, alkyl of 1 to 4 carbon atoms and alkoxy of 1 to 4 carbon atoms; and R6 and R7, which can be the same or different, are each selected from hydrogen and alkyl 1 to 3 carbon atoms.
The compounds are useful as growth promoting agents in animals.
Description
3~787 1514-1 04A II()RPHOLINE COMPOUNDS AND METHOD OF tlSE
PP: 57~
BACKGROUND OF THE INVENTION
This invention relates to morpholine derivatlves and, more specifically, to a y-phenyl-~-9~3-(4-methyl~-5 dioxolan-butyric acid amide, the method of its prepara-tion, its use as a growth stimulant in animals, and improvement of feed-utilization.
It is an objective of the meat production industry to stimulate the growth of animals and to improve utilization of feed. It is known that agents with estro-genic activity can be used for this purpose; these agents, however, have been banned recently by numerous countries because they sometimes produce serious side effects.
Various other agents, or groups of agents, are currently being used as growth promoters in a number of animal species. For the rearing of swine, for example, quinoxalines are used, as described by ~addadin et al.
~British Patent No. 1,305,138), by A. Garzia and R Do 20 Williams (~.S. Patent No. 4,128,642) and others. V.SO
Patent No. 3,232,345 to Hodge et al. discloses the use of zearalanol as a growth-promoting agent in cattle and sheep. Bacitracin derivatives are used as growth-promoting agents in chickens.
Where the quinoxalines, the antibiotics, and their derivatives are concerned, most of the growth stimulating action is based on the health status of the treated animals and this treatment does not provide ~or improve-ment of the diet-conversion factor. ~urthermore, these compounds cause environmental ecological problems.
Currently used anabolic agents are known to act by means of an undesirable horrnonal function.
Another disadvantage of currently used growth stimulants is that they frequently are active only in limited species, in some cases only in a single animal `` c i31 ~7 species. Frequently, they do not provide for improvement of conversion of food into meat.
There is still a need for agents which ~timulate the growth of animals without the disadvantages associated with presently used products, and which can be used in several animal species with satisfactory results.
Sl)MMARY OF TH~ INVENTION
In accordance with the invention, there are provided morpholine derivatives~ specifically, cyclic amides of y-phenyl~ -1,3-dioxolan butyric acids. There is also provided a method for their preparation. The compounds of the invention are useful a~ growth promoters in various animal species.
The preferred compound is a ~-phenyl-~-1,3-~4-methyl)-dioxolanbutyric acidamide obtained by reacting ~-benzoylpropionic acid morpholinamide ~ith 1~2-propylene glycol in the presence of p-toluenesulfonic acid.
DESCRIPTION OF THE INVENTION
We have found that the cyclic y-phenyl~ -1,3-dioxolan butyric acid amides of the invention are capable of stimulating growth factors in several animal species without exhibiting hormonal or chemotherapeutic activities, and without causing ecological problems~ Tl1e subject compounds also exhibit anti-stress activity. The compounds exhibit very low toxicity.
They are metabolized rapidly and the metabolites have minimal toxicity.
The compounds of the invention have the general formula I.
3 ~ 31~7~7 -/H - CH-~O O
R3 ~ -- \ C ~~ CH2 --- CH2 -- CO -- N 3 (I) wherein Rl, R2~ R3, ~ and ~ , which can be the same or different, are each selected from hydrogen, al~yl from 1 to 4 carbon atoms and alkoxy from 1 to 4 carbon atoms;
and ~ and R7, which can be the same or different, are each selected from hydrogen and alXyl from 1 to 3 carbon atoms.
The compounds are obtained by the reaction of B-benzoylpropionic acid morphonylamide with 1,2-glycols such as ethylene glycol, propylene glycol, etc. ~he reaction is preferably carried out in a suitable solvent such as benzene at boiling temperature for about 50 hours, in the presence of a catalyst such as p-toluenesulfonic acid monohydrate. The presence of a large excess of glycol is essential, and the reaction is facilitated by removal of the water formed while the reaction is in progress.
The preferred compound of the invention is a y-phenyl-y-1,3-(4-methyl)-dioxolanbutyric acid amide with the formula II.
~~- t CH3 ~ - C __ C~32 -- CH2 -- CO -- N O (II) - ( :
~31~787 This compound is obtaine~ by treatlng a quantity (equivalent) of amide with a ~0-30 fold excess of propylene glycol in a quantity of benzene equal to a 4-8 fold volume of the propylene glycol. The reaction is carried out in the presence of a small quantity of p-toluenesulfonic acid monohydrate, at reflux for 50 hours with azeotropic distillation of the water formed during the reaction.
In a number of tests, the toxicity of the compound of formula II was found to be extremely low in relation to the "dosage" that was used: the LD50 in the mouse for i.p. administration is 565 mg/Xg, while the p.o. toxicity is 9SS mg/kg.
A dosage of 100 mg/kg, i.p., has a sedative action in the rat. Upon administration in rats, we observed a significant increase of the B-endorphin level in the left nucleus; this is believed to be the cause of the growth stimulating activity since the relation between increased ~-endorphin levels and the production of growth hormone is well known.
The compound of the inver.tion is administered to animals to promote growth. The compound is capable of stimulating the desire for fo~ in the treated animals, and producing a better feed-conversion index in cattle, swine, horses, sheep, and chickens. The ratio for meat/fat/bone remains unchanged in animal~ treated with the compound. The animals are treated by i m. injection or p.o. administration with food, or by implantation.
Advantageously, solutions of 2~ in propylene glycol are 0 used for injections, with each animal receiving 2.5-1.0 mg/kg active component.
Injections are administered when treatment is initiated, after about 15 days, and again after about 30 days. On day 60, compared to the controls, the status of nutrition is equivalent to that of untreated controls 7 ~ 7 receiving the same diet, while there is a 12-15~ weight increase compared to the controls. These results were obtained in cattle, swine, horses, sheep, rodents, and chicken~.
- 5 P.o. treatment allows the use of about a 10-time~
higher dose of the active component. The compound is mixed daily with the diet for a total of about 30 days.
Treatment with the compound of the invention dose not preclude -- and is compatible with -- drug therapy, e.g., antibiotics, vitamins, etc.
The treated ani~als are specifically resistant to stress during transport, changes in weather, or stabling.
The following examples are intended to illustrate further the practice of the invention and are not intended ~o limit its scope in any way.
EXAMPL~ I
Preparation of Compound of Formula II
24.7 9 B-ben~oyl propionic acid morpholinamide (0.1 20 mole) were boiled at reflux for 50 hours with 500 mL
anhydrous benzene, 70 mL 1,2-propylene glycol, and 0~5 9 p-toluenesulfonic acid monohydrate with stirring, using a water separator.
The reaction mixture was then evaporated to 1/3 of ~5 the initial volume at reduced pressure and poured into about 100 g cracked ice. The organic layer was separated and cooled to about 10C after further evaporation.
After standing overnight at about 10'C, 22.0 g product were obtained by centrifugation and after drying in vacuo 3~ (yield, 70g of the theoretical).
The product had the appearance of a wax, and both the N.M.R. and I.R. spectra confirmed the anticipated structure. The compound was soluble in methanol, ethanol, ben~ene, glycols and D.M.F.
6 13~5787 EXAMPL~ II
i.m. Treatment of Cattle A total of 10 bull~, mean weight 500 kg, were treated i.m. with 10 mL of a 2~ solution of compo~nd II, and fed the same diet as 10 other bulls with the same weight, serving as controls. ~reatment was repeated on day 15 from initiation, and repeated once again on day 30. The animals were weighed on day 60 indicating a weight 13~ higher than that of the controls. When the animals were butchered, the organs of the treated animals did not indicate any abnormalities; the ratio of meat-to-fat remained unchanged.
PP: 57~
BACKGROUND OF THE INVENTION
This invention relates to morpholine derivatlves and, more specifically, to a y-phenyl-~-9~3-(4-methyl~-5 dioxolan-butyric acid amide, the method of its prepara-tion, its use as a growth stimulant in animals, and improvement of feed-utilization.
It is an objective of the meat production industry to stimulate the growth of animals and to improve utilization of feed. It is known that agents with estro-genic activity can be used for this purpose; these agents, however, have been banned recently by numerous countries because they sometimes produce serious side effects.
Various other agents, or groups of agents, are currently being used as growth promoters in a number of animal species. For the rearing of swine, for example, quinoxalines are used, as described by ~addadin et al.
~British Patent No. 1,305,138), by A. Garzia and R Do 20 Williams (~.S. Patent No. 4,128,642) and others. V.SO
Patent No. 3,232,345 to Hodge et al. discloses the use of zearalanol as a growth-promoting agent in cattle and sheep. Bacitracin derivatives are used as growth-promoting agents in chickens.
Where the quinoxalines, the antibiotics, and their derivatives are concerned, most of the growth stimulating action is based on the health status of the treated animals and this treatment does not provide ~or improve-ment of the diet-conversion factor. ~urthermore, these compounds cause environmental ecological problems.
Currently used anabolic agents are known to act by means of an undesirable horrnonal function.
Another disadvantage of currently used growth stimulants is that they frequently are active only in limited species, in some cases only in a single animal `` c i31 ~7 species. Frequently, they do not provide for improvement of conversion of food into meat.
There is still a need for agents which ~timulate the growth of animals without the disadvantages associated with presently used products, and which can be used in several animal species with satisfactory results.
Sl)MMARY OF TH~ INVENTION
In accordance with the invention, there are provided morpholine derivatives~ specifically, cyclic amides of y-phenyl~ -1,3-dioxolan butyric acids. There is also provided a method for their preparation. The compounds of the invention are useful a~ growth promoters in various animal species.
The preferred compound is a ~-phenyl-~-1,3-~4-methyl)-dioxolanbutyric acidamide obtained by reacting ~-benzoylpropionic acid morpholinamide ~ith 1~2-propylene glycol in the presence of p-toluenesulfonic acid.
DESCRIPTION OF THE INVENTION
We have found that the cyclic y-phenyl~ -1,3-dioxolan butyric acid amides of the invention are capable of stimulating growth factors in several animal species without exhibiting hormonal or chemotherapeutic activities, and without causing ecological problems~ Tl1e subject compounds also exhibit anti-stress activity. The compounds exhibit very low toxicity.
They are metabolized rapidly and the metabolites have minimal toxicity.
The compounds of the invention have the general formula I.
3 ~ 31~7~7 -/H - CH-~O O
R3 ~ -- \ C ~~ CH2 --- CH2 -- CO -- N 3 (I) wherein Rl, R2~ R3, ~ and ~ , which can be the same or different, are each selected from hydrogen, al~yl from 1 to 4 carbon atoms and alkoxy from 1 to 4 carbon atoms;
and ~ and R7, which can be the same or different, are each selected from hydrogen and alXyl from 1 to 3 carbon atoms.
The compounds are obtained by the reaction of B-benzoylpropionic acid morphonylamide with 1,2-glycols such as ethylene glycol, propylene glycol, etc. ~he reaction is preferably carried out in a suitable solvent such as benzene at boiling temperature for about 50 hours, in the presence of a catalyst such as p-toluenesulfonic acid monohydrate. The presence of a large excess of glycol is essential, and the reaction is facilitated by removal of the water formed while the reaction is in progress.
The preferred compound of the invention is a y-phenyl-y-1,3-(4-methyl)-dioxolanbutyric acid amide with the formula II.
~~- t CH3 ~ - C __ C~32 -- CH2 -- CO -- N O (II) - ( :
~31~787 This compound is obtaine~ by treatlng a quantity (equivalent) of amide with a ~0-30 fold excess of propylene glycol in a quantity of benzene equal to a 4-8 fold volume of the propylene glycol. The reaction is carried out in the presence of a small quantity of p-toluenesulfonic acid monohydrate, at reflux for 50 hours with azeotropic distillation of the water formed during the reaction.
In a number of tests, the toxicity of the compound of formula II was found to be extremely low in relation to the "dosage" that was used: the LD50 in the mouse for i.p. administration is 565 mg/Xg, while the p.o. toxicity is 9SS mg/kg.
A dosage of 100 mg/kg, i.p., has a sedative action in the rat. Upon administration in rats, we observed a significant increase of the B-endorphin level in the left nucleus; this is believed to be the cause of the growth stimulating activity since the relation between increased ~-endorphin levels and the production of growth hormone is well known.
The compound of the inver.tion is administered to animals to promote growth. The compound is capable of stimulating the desire for fo~ in the treated animals, and producing a better feed-conversion index in cattle, swine, horses, sheep, and chickens. The ratio for meat/fat/bone remains unchanged in animal~ treated with the compound. The animals are treated by i m. injection or p.o. administration with food, or by implantation.
Advantageously, solutions of 2~ in propylene glycol are 0 used for injections, with each animal receiving 2.5-1.0 mg/kg active component.
Injections are administered when treatment is initiated, after about 15 days, and again after about 30 days. On day 60, compared to the controls, the status of nutrition is equivalent to that of untreated controls 7 ~ 7 receiving the same diet, while there is a 12-15~ weight increase compared to the controls. These results were obtained in cattle, swine, horses, sheep, rodents, and chicken~.
- 5 P.o. treatment allows the use of about a 10-time~
higher dose of the active component. The compound is mixed daily with the diet for a total of about 30 days.
Treatment with the compound of the invention dose not preclude -- and is compatible with -- drug therapy, e.g., antibiotics, vitamins, etc.
The treated ani~als are specifically resistant to stress during transport, changes in weather, or stabling.
The following examples are intended to illustrate further the practice of the invention and are not intended ~o limit its scope in any way.
EXAMPL~ I
Preparation of Compound of Formula II
24.7 9 B-ben~oyl propionic acid morpholinamide (0.1 20 mole) were boiled at reflux for 50 hours with 500 mL
anhydrous benzene, 70 mL 1,2-propylene glycol, and 0~5 9 p-toluenesulfonic acid monohydrate with stirring, using a water separator.
The reaction mixture was then evaporated to 1/3 of ~5 the initial volume at reduced pressure and poured into about 100 g cracked ice. The organic layer was separated and cooled to about 10C after further evaporation.
After standing overnight at about 10'C, 22.0 g product were obtained by centrifugation and after drying in vacuo 3~ (yield, 70g of the theoretical).
The product had the appearance of a wax, and both the N.M.R. and I.R. spectra confirmed the anticipated structure. The compound was soluble in methanol, ethanol, ben~ene, glycols and D.M.F.
6 13~5787 EXAMPL~ II
i.m. Treatment of Cattle A total of 10 bull~, mean weight 500 kg, were treated i.m. with 10 mL of a 2~ solution of compo~nd II, and fed the same diet as 10 other bulls with the same weight, serving as controls. ~reatment was repeated on day 15 from initiation, and repeated once again on day 30. The animals were weighed on day 60 indicating a weight 13~ higher than that of the controls. When the animals were butchered, the organs of the treated animals did not indicate any abnormalities; the ratio of meat-to-fat remained unchanged.
Claims (14)
1. A compound of the formula wherein R1, R2, R3, R4 and R5 , which can be the same or different, are each selected from hydrogen, alkyl of 1 to 4 carbon atoms and alkoxy of 1 to 4 carbon atoms; and R6 and R7, which can be the same or different, are each selected from hydrogen and alkyl 1 to 3 carbon atoms.
2. The compound of the formula
3. A method of promoting the growth of an animal which comprises administering to the animal a growth-promoting amount of a compound of the formula wherein R1, R2, R3, R4 and R5 , which can be the same or different, are each selected from hydrogen, alkyl of 1 to 4 carbon atoms and alkoxy of 1 to 4 carbon atoms; and R6 and R7, which can be the same or different, are each selected from hydrogen and alkyl 1 to 3 carbon atoms.
4. A method as claimed in claim 3 wherein the compound has the formula
5. A method as claimed in claim 3 wherein the compound is administered orally.
6. A method as claimed in claim 3 wherein the compound is administered by injection.
7. A method for preparing a growth-promoting compound which comprises reacting .beta.-benzoylpropionic acid morpholinamide with 1,2-propylene glycol in the presence of p-toluenesulfonic acid.
8. A growth promoting composition comprising a compound of the formula wherein R1, R2, R3, R4 and R5, which can be the same or different, are each selected from hydrogen, alkyl of 1 to 4 carbon atoms and alkoxy of 1 to 4 carbon atoms; and R6 and R7, which can be the same or different, are each selected from hydrogen and alkyl 1 to 3 carbon atoms, in admixture with a carrier or diluent therefor.
9. A composition, as claimed in claim 8, which is suitable for oral administration.
10. A composition, as claimed in claim 8, which is suitable for administration by injection.
11. A composition, as claimed in claim 10, which is a solution of said compound in propylene glycol.
12. A composition, as claimed in claim 9, wherein the carrier or diluent is a food.
13. A composition, as claimed in claim 8, which is suitable for administration as an implant.
14. A composition, as claimed in claim 8, 9 or 10, wherein the compound is
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US07/111,656 US4753937A (en) | 1986-01-27 | 1987-10-23 | Morpholine compounds and method of promoting animal growth |
| US111,656 | 1987-10-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1315787C true CA1315787C (en) | 1993-04-06 |
Family
ID=22339733
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000569596A Expired - Fee Related CA1315787C (en) | 1987-10-23 | 1988-06-15 | Morpholine compounds and methods of use |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1315787C (en) |
-
1988
- 1988-06-15 CA CA000569596A patent/CA1315787C/en not_active Expired - Fee Related
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKLA | Lapsed | ||
| MKLA | Lapsed |
Effective date: 19951008 |