2-acylaminopropanol compound and medical composition

• US 5,763,438 A
• Filed: 12/09/1996
• Issued: 06/09/1998
• Est. Priority Date: 06/10/1994
• Status: Expired due to Term

• Current Assignee: Seikagaku Corporation
• Original Assignee: Seikagaku Corporation
• Inventors: Yamada, Haruki, Nagai, Takayuki, Inokuchi, Jinichi, Jinbo, Masayuki
• Primary Examiner(s): Ramsuer, Robert W.
• Application Number:
  US08/750,699
• Time in Patent Office: 547 Days
• Field of Search: 544/168, 554/55, 514/237.8
• US Class Current: 514/237.8
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07C 233/36 having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07D 207/12 Oxygen or sulfur atoms
• CPC Class Codes: C07D 211/22 by oxygen atoms
• CPC Class Codes: C07D 211/46 having a hydrogen atom as the second substituent in position 4
• CPC Class Codes: C07D 295/125 with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
• CPC Class Codes: C07D 295/185 from aliphatic carboxylic acids
• CPC Class Codes: Y10S 977/798 having internalized material
• CPC Class Codes: Y10S 977/904 for medical, immunological, body treatment, or diagnosis
• CPC Class Codes: Y10S 977/915 Therapeutic or pharmaceutical composition

Abstract

This invention relates to a 2-acylaminopropanol compound represented by the formula (I): ##STR1## (wherein R¹ represents a phenyl group which may be substituted by 1 to 3 same or different substituents selected from alkyl, alkoxy, hydroxyl, hydroxyalkyl and nitro, R² represents the following formula (II), (III), (IV), (V) or (VI), ##STR2## (wherein R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, m and p are those defined in the specification) R¹¹ represents a hydrogen atom or a hydroxyl group, and n represents an integer of 3 to 15) or a pharmaceutically acceptable salt thereof.

Claims

1. A 2-acylaminopropanol compound of the formula ##STR17## wherein R¹ is phenyl optionally substituted by 1 to 3 members selected from the group consisting of alkyl, alkoxy, hydroxyl, hydroxyalkyl and nitro, R² is a formula selected from the group consisting of ##STR18## wherein R³ and R⁴ are individually selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, hydroxycycloalkyl, aralkyl and piperazino optionally substituted by alkyl, R⁵ is 1 or 2 substituents selected from the group consisting of hydrogen, hydroxyl, lower alkyl, alkoxy, hydroxyalkyl, carboxy, alkoxycarbonyl, aralkyl, piperidino, acyloxy, of an organic carboxylic acid amino and aminoalkyl, R⁶ is hydrogen or 1 or 2 substituents of R⁵, R⁷ is alkylene optionally interrupted by oxygen, R⁸ and R⁹ are individually selected from the group consisting of hydrogen, lower alkyl and hydroxy-lower alkyl, or R⁸ and R⁹ together with the nitrogen atom to which they are bonded form a piperidino or morpholino optionally substituted by lower alkyl, m is an integer of 2 to 6, p is 2 or 3, X is ##STR19## wherein R¹⁰ is selected from the group consisting of hydrogen, lower alkyl, acyl, lower alkoxycarbonyl and pyridyl, R¹¹ is hydrogen or hydroxyl and n is an integer of 3 to 15) or a non-toxic, pharmaceutically acceptable salt thereof.

2. The 2-acylaminopropanol compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R¹ is phenyl optionally substituted by 1 or 2 hydroxyl or alkyl or alkoxy of 1 to 4 carbon atoms.

3. The 2-acylaminopropanol compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R¹ is phenyl group optionally substituted by 1 or 2 hydroxyl groups or methoxy groups.

4. The 2-acylaminopropanol compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R² is a substituent of formula (II), and R³ and R⁴ are selected from the group consisting of alkyl of 1 to 6 carbon atoms, alkenyl of 3 to 4 carbon atoms, alkoxyalkyl of 3 to 6 carbon atoms, cycloalkyl of 5 to 8 carbon atoms and phenylalkyl of 7 to 9 carbon atoms.

5. The 2-acylaminopropanol compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R² is a substituent of formula (II), and R³ and R⁴ are individually selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, heptyl, hexyl, allyl, 1-propenyl, 2-butenyl, hydroxyethyl, methoxyethyl, ethoxyethyl, aminoethyl, cyclopentyl, cyclohexyl, 4-hydroxycyclohexyl, benzyl, α

-methylbenzyl piperazino and 4-methyl-piperazino.

6. The 2-acylaminopropanol compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R² is amino;

methylamino, ethylamino, isopropylamino, isobutylamino, dimethylamino, diethylamino-, dipropylamino, methyl(ethyl)amino;

2-hydroxyethylamino, bis(2-hydroxyethyl)amino;

2-aminoethylamino;

cyclohexylamino, 4-hydroxycyclohexylamino;

benzylamino or α

-methylbenzylamino.

7. The 2-acylaminopropanol compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R² is a substituent of formula, and R⁵ is selected from the group consisting of alkyl of 1 to 4 carbon atoms, methoxy, ethoxy, hydroxymethyl, 2-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, benzyl acetoxy and aminomethyl.

8. The 2-acylaminopropanol compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R² is selected from the group consisting of ethyleneimino, azetidino, pyrrolidino, piperidino, azepino, 2- or 3-hydroxypyrrolidino, 2-hydroxymethyl-pyrrolidino, 2-, 3- or 4-hydroxypiperidino, 3, 4-dihydroxy piperidino, 2-, 3- or 4-hydroxymethylpiperidino, 2-, 3- or 4-hydroxyethylpiperidino, 2-, 3- or 4-methylpiperidino, 3,5-dimethylpiperidino, 3-hydroxymethyl-4,5-dihydroxy-piperidino, 2-hydroxymethyl-3,4,5-trihydroxypiperidino, 4-methoxypiperidino, 4-methoxycarbonylpiperidino, 4-carboxypiperidino, 4-ethyoxycarbonylpiperidino, 4-benzylpiperidino or 4-piperidinopiperidino.

9. The 2-acylaminopropanol compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R² is a substituent of formula (IV) and is selected from the group consisting of 4-thiazinyl, thiomorpholino, piperazino, N-methylpiperazino, N-methoxycarbonylpiperazino, N-ethyoxycarbonylpiperazino, N-(2-pyridyl)piperazino, N-formylpiperazino, N-acetylpiperazino and N-methyl-1,4-diazacycloheptan-1-yl.

10. The 2-acylaminopropanol compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R² is a substituent of formula (VI) and is selected from the group consisting of 2-(dimethylamino)ethylamino, 2-(methylamino)ethylamino, 2-(diethylamino)ethylamino, 2-(ethylamino)ethylamino, 3-(dimethylamino)propylamino, 3-(diethylamino)propylamino, 3-(dibutylamino)propylamino, 3- di!bis(2-hydroxyethyl)amino!-propylamino, 3-2-dimethylamino)ethoxy)propylamino, 2-piperidinoethylamino, 2-(4-methylpiperidino)ethylamino, 3-piperidinopropylamino, 3-(2-methylpiperidino)propylamino, 3-(4-methylpiperidino)propylamino, 2-morpholinoethylamino and 3- morpholinopropylamino.

11. The 2-acylaminopropanol compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein

R¹ is phenyl optionally substituted by 1 to 2 substituents selected from the group consisting of hydroxyl and methoxy,

R² is formula (II), (III), or (IV) wherein

in the formula (II), R³ and R⁴ are the same alkyl of 1 to 3 carbon atoms or R³ is hydrogen and R⁴ is cycloalkyl or hydroxycycloalkyl of 5 to 6 carbon atoms;

in the formula (III), R¹ is hydrogen or hydroxyl and m is 4 or 5,

in the formula (IV), p is 2, X is formula (VII) and R¹⁰ is methyl,

R¹¹ is hydrogen and n is an integer of 5 to 13.

12. The 2-acylaminopropanol compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R¹ is phenyl optionally substituted by 1 to 2 substituents selected from the group consisting of hydroxyl and methoxy, R² is a dimethylamino group, a diethylamino group, a cyclohexylamino group, a 4-hydroxycyclohexylamino group, a pyrrolidino group, a 3-hydroxypyrrolidino group, a piperidino group, a 4-hydroxypiperidino group or a N-methylpiperazino group;

R¹¹ is a hydrogen atom; and

n is an integer of 5 to 13.

13. The 2-acylaminopropanol compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R¹ is phenyl, R² is selected from the group consisting of diethylamino, 4-hydroxypiperidino, N-methylpiperazino and 3-hydroxypyrrolidino, R¹¹ is hydrogen, and n is 5 to 13.

14. A medical composition which comprises the 2-acylaminopropanol compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

15. The medical composition according to claim 14, wherein the 2-acylaminopropanol compound according to claim 1 or a pharmaceutically acceptable salt thereof is administered in an amount of 0.25 to 200 mg/kg per day.

16. The medical composition according to claim 15, wherein the 2-acylaminopropanol compound according to claim 1 or a pharmaceutically acceptable salt thereof is administered in an amount of 0.5 to 100 mg/kg per day.

17. An antiviral agent which comprises the 2-acylaminopropanol compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

18. The antiviral agent according to claim 17, wherein in the formula (I), R¹ is phenyl optionally substituted by 1 to 2 hydroxyl or methoxy, R² is selected from the group consisting of dimethylamino, diethylamino, dipropylamino, piperidino, 4-hydroxypiperidino and 2-hydroxymethylpiperidino, R¹¹ is hydrogen or hydroxyl and n is an integer of 5 to 13, and the compound is a D-erythro isomer (1S, 2R) or a L-erythro isomer (1R, 2S).

19. The antiviral agent according to claim 17, wherein in the formula (I), R¹ is a phenyl group;

R² is a diethylamino group or a 4-hydroxypiperidino group;

R¹¹ is a hydrogen atom; and

n is an integer of 7 to 13, and the compound is a D-erythro isomer (1S, 2R).

20. An agent for treating neuronal diseases, which comprises the 2-acylaminopropanol compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

21. The agent for treating neuronal diseases according to claim 20, wherein in the formula (I), R¹ is phenyl optionally substituted by 1 to 2 hydroxyl or methoxy, R² is selected from the croup consisting of 4-hydroxycyclohexylamino, 3-hydroxypyrrolidino, 4-hydroxypiperidino, 3,4-dihydroxypiperidino, 3,4,5-trihydroxypiperidino, 3-hydroxymethyl-4,5-dihydroxypiperidino and N-methylpiperazino, R¹¹ is hydrogen or hydroxyl and n is an integer of 5 to 13, and the compound is L-threo isomer (1S, 2S), a D-erythro isomer (1S, 2R) or a L-erythro isomer (1R, 2S).

22. The agent for treating neuronal diseases according to claim 20, wherein in the formula (I), R¹ is phenyl, R² is selected from the group consisting of 4-hydroxycyclohexylamino, 3-hydroxypyrrolidino, 4-hydroxypiperidino and N-methylpiperazino R¹¹ is hydrogen and n is an integer of 5 to 13, and the compound is the L-threo isomer (1S, 2S).

23. The agent for treating neuronal diseases according to claim 20, wherein in the formula (I), R¹ is phenyl optionally substituted by 1 to 2 hydroxyl or methoxy, R² is selected from the group consisting of cyclohexylamino, pyrrolidino and piperidino, R¹¹ is hydrogen or hydroxyl and n is an integer of 5 to 13, and the compound is the D-threo isomer (1R, 2R).

24. The agent for treating neuronal diseases according to claim 20, wherein in the formula (I), R¹ is phenyl, R² is selected from the group consisting of cyclohexylamino, pyrrolidino and piperidino group;

R¹¹ is hydrogen and n is an integer of 7 to 13, and the compound is a D-threo isomer (1R, 2R).

25. A method of treating viral infectious diseases in warm-blooded animals which comprises administering to warm-blooded animals an antivirally effective amount of a 2-acylaminopropanol compound according to claim 1 or a pharmaceutically acceptable salt thereof which are infected with viruses.

26. A method of treating neuronal diseases in mammals which comprises administering to mammals an amount of a 2-acylaminopropanol compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof effective for accelerating biosynthesis of glycosphingolipids, accelerating neurite extension and/or accelerating synapse formation which suffer form neuronal diseases caused by disorders of peripheral nervous system or central nervous system.

27. The 2-acylaminopropanol compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R² is a substituent of formula (VI), the alkylene optionally interrupted by oxygen, of R⁷ is selected from the group consisting of ethylene, trimethylene and --(CH₂)_q --O--(CH₂)_r --, q and r individually are 2 or 3, R⁸ and R⁹ are individually selected from the group consisting of methyl, ethyl, propyl, butyl and 2-hydroxyethyl, and R⁸ and R⁹ are together with the nitrogen atom to which they are bonded selected from the group consisting of piperidino, 2-, 3- or 4-methylpiperidino and morpholino.