US 4,987,153 AGrant
Alkylaminoamide Compounds
Issue Date:1991-01-22
•12 Claims
Abstract
Novel alkylaminoamides of the formula ##STR1## wherein R is selected from the group consisting of (a) alkyl of 1 to 8 carbon atoms, (b) cycloalkyl of 3 to 7 carbon atoms optionally substituted with phenyl, (c) aryl of 6 to 14 carbon atoms optionally substituted with at least one member of the group consisting of halogen, --CF.sub.3, alkyl of 1 to 6 carbon atoms, --NO.sub.2 and cycloalkyl of 3 to 7 carbon atoms, (d) aralkyl of 7 to 14 carbon atoms and (e) ##STR2## Z is --(CH.sub.2).sub.n -- optionally substituted by an alkyl of 1 to 6 carbon atoms, n is an integer from 1 to 6, Y is --(CH.sub.2).sub.n -- or ##STR3## and their non-toxic, pharmaceutically acceptable acid addition salts having remarkable anti-oedematous and anti-inflammatory activity.
Metadata
Assignee
- Roussel Uclaf
Inventors
- David P. Kay
- Peter D. Kennewell
Application Information
Application Number:US 2299224
Filing Date:1988-08-08
Priority Date:1985-07-15
Art Unit:129
Classifications
IPC:
A61K 31165C07C23300
Field of Search:
564163;164;166;620
Patent Drawings
This patent does not have any drawings.
Description
EXAMPLE 1
N-(1,2,3,4,4a,9a-hexahydro-4,4,4a,9-tetramethylcarbazol-2.beta.-yl)-3-(tran s-4-phenylcyclohexylamino)-propionamide and its hydrochloride
STEP A: 2-amino-1,2,3,4,4a,9a-hexahydro-4,4,4a,9-tetramethyl carbazole
A mixture of 22 g of 3,4,4a,9a-tetrahydro-4,4,4a,9-tetramethylcarbazol-2-(1H)-one prepared as in J. Chem. Soc., 1955, 4369, 37 g of ammonium acetate and 4 g of sodium cyanoborohydride in 300 ml of methanol was stirred overnight at room temperature under nitrogen. The mixture was concentrated to 70 ml, diluted with 600 ml of water, acidified to pH of 1 with concentrated HCl and stirred at room temperature for 1 hour. The mixture was extracted with ether, adjusted to a pH of 5 with concentrated ammonia, further extracted with ether and then adjusted to a pH of 10 with concentrated ammonia. Extraction with ether then gave 11 g of a 50% mixture of .alpha.- and .beta.-2-amino-1,2,3,4,4a,9a-hexahydro-4,4,4a,9-tetramethylcarbazole as a pale yellow oil.
STEP B: N-(1,2,3,4,4a,9a-hexahydro-4,4,4a,9-tetramethylcarbazol-2.beta.-yl)-3-chlo ropropionamide
A mixture of 24.4 g of 2-amino-1,2,3,4,4a,9a-hexahydro-4,4,4a,9-tetramethylcarbazole and 25 g of potassium carbonate was stirred in 300 ml of dichloromethane while 14 g of 3-chloropropionyl chloride are added dropwise. The mixture was stirred overnight at room temperature and poured into water. The organic layer was washed with 2N hydrochloric acid and aqueous sodium bicarbonate, dried over MgSO.sub.4 and evaporated to dryness to give a colorless solid. The solid was subjected to HPLC on "Lichoprep" in dichloromethane to yield first 6 g (18%) of N-(1,2,3,4,4a,9a-hexahydro-4,4,4a,9-tetramethylcarbazol-2.beta.-yl)-3-chlo ropropionamide melting at 168.degree.-70.degree. C., .mu..sub.max 3260 and 1630 cm.sup.-1, and then 12 g (36%) of N-(1,2,3,4,4a,9a-hexahydro-4,4,4,4a,9-tetramethylcarbazol-2.beta.-yl)-3-ch loropropionamide melting at 166.degree.-8.degree. C., .nu..sub.max 3215 and 1630 cm.sup.-1
STEP C: N-(1,2,3,4,4a,9a-hexahydro-4,4,4a,9-tetramethylcarbazol-2.beta.-yl)-3-(tra ns-4-phenylcyclohexylamino)-propionamide
1.5 g of N-(1,2,3,4,4a,9a-hexahydro-4,4,4a,9-tetramethylcarbazol-2.beta.-yl)-3-chlo ropropionamide and 3 g of trans-4-phenylcyclohexylamine prepared as in J. Org. Chem. (1952) 17, 1017 were stirred under reflux in dry toluene for 3 days. The cooled reaction mixture was filtered and evaporated to dryness under reduced pressure. The residue was chromatographed on silica and elution with dichloromethane-methanol (95:5) gave 1.36g (66%) of N-(1,2,3,4,4a,9a-hexahydro-4,4,4a,9-tetramethylcarbazol-2.beta.-yl)-3-(tra ns-4-phenylcyclohexylamino)-propionamide as a colorless oil. The oil was dissolved in methanol and treated with ethereal hydrogen chloride to give the colorless, hygroscopic, crystalline hydrochloride salt melting at 184.degree.-6.degree. C. .nu..sub.max. 3410, 3265, 1680 cm.sup.-1.
EXAMPLES 2 TO 20
Using the process of Example 1 but starting from the appropriate amines of formulae II and V and acid chlorides of formula III, the following compounds were prepared:
EXAMPLE 2
N-(1,2,3,4,4a,9a-hexahydro-4,4,4a,9-tetramethylcarbazol-2.alpha.-yl)-3-(tra ns-4-phenylcyclohexylamino)-propionamide.
EXAMPLE 3
N-(1,2,3,4,4a,9a-hexahydro-4,4,4a,9-tetramethylcarbazol-2.beta.-yl)2-(trans -4-phenylcyclohexylamino)-acetamide.
EXAMPLE 4
N-(1,2,3,4,4a,9a-hexahydro-4,4,4a,9-tetramethylcarbazol-2.alpha.-yl)-2-(tra ns-4-phenylcyclohexylamino)-acetamide.
EXAMPLE 5
N-(1,2,3,4,4a,9a-hexahydro-4,4,4a,9-tetramethylcarbazol-2.beta.-yl)-3-(4-ph enylbutylamino)-propionamide.
EXAMPLE 6
N-(1,2,3,4,4a,9a-hexahydro-4,4,4a,9-tetramethylcarbazol-2.alpha.-yl)-3-(4-p henylbutylamino)-propionamide.
EXAMPLE 7
N-(1,2,3,4,4a,9a-hexahydro)-4,4,4a,9-tetramethylcarbazol-2.beta.-yl)-3-(3-p henylpropylamino)-propionamide.
EXAMPLE 8
N-(1,2,3,4,4a,9a-hexahydro-4,4,4a,9-tetramethylcarbazol-2.alpha.-yl)-3-(3-p henylpropylamino)-propionamide.
EXAMPLE 9
N-(1,2,3,4,4a,9a-hexahydro-4,4,4a,9-tetramethylcarbazol-2.beta.-yl)-2-(4-ph enylbutylamino)-acetamide.
EXAMPLE 10
N-(1,2,3,4,4a,9a-hexahydro-4,4,4a,9-tetramethylcarbazol-2.alpha.yl)-2-(4phe nylbutylamino)-acetamide.
EXAMPLE 11
N-cyclohexyl-3-(trans-4-phenylcyclohexylamino)-propionamide.
EXAMPLE 12
N-phenyl-3-(trans-4-phenylcyclohexylamino)-propionamide.
EXAMPLE 13
N-n-hexyl-3-(trans-4-phenylcyclohexylamino)-propionamide.
EXAMPLE 14
N-(4-chlorophenyl)-3-(trans-4-phenylcyclohexylamino)-propionamide.
EXAMPLE 15
N-(4-cyclohexylphenyl)-3-(trans-4-phenylcyclohexylamino)-propionamide.
EXAMPLE 16
N-(3,4-dichlorophenyl)-3-(trans-4-phenylcyclohexylamino)-propionamide.
EXAMPLE 17
N-(4-phenylcyclohexyl)-3-(trans-4-phenylcyclohexylamino)-propionamide.
EXAMPLE 18
N-(3-trifluoromethyl-4-chlorophenyl)-3-(trans-4-phenylcyclohexylamino)-prop ionamide.
EXAMPLE 19
N-(4-chlorophenyl)-4-trans-4-phenylcyclohexylamino)-butyramide
EXAMPLE 20
N-(3-trifluoromethyl-4-nitrophenyl)-3-(trans-4-phenylcyclohexylamino)-propi onamide.
The properties of the said products are reported in the following Table.
NOTE: Analysis of salts of the carbazole amides was difficult due to hygroscopicity and analysis of their free bases was complicated by their non-crystalline nature and consequential occlusion of dichloromethane.
EXAMPLE 21
Tablets were prepared containing 20 mg of the compound of Example 1 or 6 and sufficient excipient of lactose, starch, talc and magnesium stearate for a final weight of 150 mg.
PHARMACOLOGICAL DATA
The anti-oedematous properties of the compounds were assessed by utilization of a modification of the carrageenin-induced oedema procedure [Proc. Soc. Exp. Biol. Med., 1962, Vol. 11, 544] following administration to male Wistar rats. The data in the following Table display the percentage inhibition by weight compared to control after a dose of 100 mg/kg p.o. or 50 mg/kg i.p.
Various modifications of the products and process of the invention may be made without departing from the spirit or scope thereof and it is to be understood that the invention is intended to be limited only as defined in the appended claims.
Claims
What we claim is:
1. A compound selected from the group consisting of alkylaminoamides of the formula ##STR24## wherein R is selected from the group consisting of (a) alkyl of 1 to 8 carbon atoms, (b) cycloalkyl of 3 to 7 carbon atoms unsubstituted or substituted with phenyl, (c) aryl of 6 to 14 carbon atoms unsubstituted or substituted with at least one member of the group consisting of halogen, --CF.sub.3, alkyl of 1 to 6 carbon atoms, --NO.sub.2 and cyclohexyl (d) aralkyl of 7 to 14 carbon atoms and (e) ##STR25## Z is linear or branched alkyl of 1 to 12 carbon atoms Y is --(CH.sub.2).sub.n -- or ##STR26## and their non-toxic, pharmaceutically acceptable acid addition salts.
2. A compound of claim 1 wherein R is selected from the group consisting of n-hexyl, cyclohexyl, phenylcyclohexyl, phenyl and phenyl substituted by one or two substituents selected from the group consisting of chlorine, cyclohexyl, trifluoromethyl and nitro; Z is selected from the group consisting of --CH.sub.2 --, --(CH.sub.2).sub.2 -- and (CH.sub.2).sub.3 -- and Y is selected from the group consisting of ##STR27## --(CH.sub.2).sub.3 -- and --(CH.sub.2).sub.4 --.
3. A compound of claim 1 wherein R is substituted phenyl, Z is selected from the group consisting of --(CH.sub.2).sub.2 -- and Y is selected from the group consisting of ##STR28## or --(CH.sub.2).sub.4 --.
4. A compound of claim 1 selected from the group consisting of N-(cyclohexyl-3-(trans-4-phenylcyclohexylamino)-propionamide; N-phenyl-3-(trans-4-phenylcyclohexylamno)-propionamide; N-n-hexyl-3-(trans-4-phenyl cyclohexylamino)-propionamide; and N-(4-chlorophenyl)-3-(trans-4-phenylcyclohexylamino)-propionamide and their non-toxic, pharmaceutically acceptable acid additions salts.
5. An antiedematous and anti-inflammatory composition comprising an antiedematously and anti-inflammatorily effective amount of at least one compound of claim 1, and an excipient.
6. A composition of claim 5 wherein R is selected from the group consisting of n-hexyl, cyclohexyl, phenylcyclohexyl, phenyl and phenyl substituted by one of two substituents selected from the group consisting of chlorine, cyclohexyl, trifluoromethyl and nitro; Z is selected from the group consisting of --CH.sub.2 --, --(CH.sub.2).sub.2 -- and (CH.sub.2).sub.3 -- Y is selected from the group consisting of ##STR29## --(CH.sub.2).sub.3 -- and --(CH.sub.2).sub.4 --.
7. A composition of claim 5 wherein R is substituted phenyl; Z is selected from the group consisting of --(CH.sub.2).sub.2 -- and Y is selected from the group consisting of ##STR30## or --(CH.sub.2 ().sub.4 --.
8. A composition of claim 5 wherein the active compound is selected from the group consisting of N-cyclohexyl-3-(trans-4-phenylcyclohexylamino)-propionamide; N-phenyl-3-(trans-4-phenylcyclohexylamino)propionamide; N-n-hexyl-3-(trans-4-phenylcyclohexylamino)-propionamide; and N-(4-chlorophenyl)-3-(trans-4-phenylcyclohexylamino-propionamide and their non-toxic, pharmaceutically acceptable acid addition salts.
9. A method of treating edema and inflammation in warm-blooded animals comprises administering to warm-blooded animals an antiedematously and anti-inflammatorily effective mount of at least one compound of claim 1.
10. A method of claim 9 wherein R is selected from the group consisting of n-hexyl, cyclohexyl, phenylcyclohexyl, phenyl and phenyl substituted by one or two substituents selected from the group consisting of chlorine, cyclohexyl, trifluoromethyl and nitro; Z is selected from the group consisting of --CH.sub.2 --, --(CH.sub.2).sub.2 -- and --(CH.sub.2).sub.3 -- and Y is selected from the group consisting of ##STR31## --(CH.sub.2).sub.3 -- and (CH.sub.2).sub.4 --.
11. A method of claim 9 wherein R is substituted phenyl; Z is selected from the group consisting of --(CH.sub.2).sub.2 -- and Y is selected from the group consisting of ##STR32## or --(CH.sub.2).sub.4 --.
12. A method of claim 9 wherein the compound is selected from the group consisting of N-cyclohexyl-3-(trans-4-phenylcyclohexylamino)-propionamide; N-phenyl-3-(trans-4-phenylcyclohexylamino)-propionamide; N-n-hexyl-3-(trans-4-phenylcyclohexylamino)-propionamide; and N-(4-chlorophenyl)-3-(trans-4-phenylcyclohexylamino)-propionamide and their non-toxic, pharmaceutically acceptable acid addition salts.
Patent Citations (1)
| Patent | Date | Inventor | Cited By |
|---|---|---|---|
| US4331816 | 1982-05-01 | Hadley |
Non-Patent Literature (2)
- Furukawa et al., "Chemical Abstracts", vol. 79, Section 31636x, Column 1 (1973).
- Large et al., "Chemical Abstracts", vol. *&, Section No. 117562x, p. 570 (1977).