Substituted tryptamines, phenalkylamines and related compounds

• US 5,403,851 A
• Filed: 04/05/1994
• Issued: 04/04/1995
• Est. Priority Date: 04/05/1994
• Status: Expired due to Fees

• Current Assignee: Interneuron Pharmaceuticals, Inc. (Endo International PLC)
• Original Assignee: Interneuron Pharmaceuticals, Inc. (Endo International PLC)
• Inventors: Locke, Kenneth W., Bellott, Emile M., Sachdeva, Yesh P., Gabriel, Richard L., Al-Farhan, Emile, Zahr, Salah A., Krishnananthan, Subramaniam, Nohrden, Michael D., D'Orlando, Kay J.
• Primary Examiner(s): Lee, Mary C.
• Assistant Examiner(s): McKane, Joseph K.
• Application Number:
  US08/223,352
• Time in Patent Office: 364 Days
• Field of Search: 548/250, 548/252, 548/253, 548/254, 548/125, 548/455, 548/457, 548/458, 548/465, 548/483, 548/492, 548/493, 548/494, 548/504, 548/506, 548/507, 514/381, 514/361, 514/414, 514/415, 514/419
• US Class Current: 514/364
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 2601/04 with a four-membered ring
• CPC Class Codes: C07C 2601/08 the ring being saturated
• CPC Class Codes: C07D 207/08 with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 209/16 Tryptamines
• CPC Class Codes: C07D 317/54 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

This invention relates to novel substituted tryptamine and phenalkylamine and related compounds, pharmaceutical compositions thereof and methods of using said compounds and compositions for a number of pharmaceutical indications including (but not limited to): 1. central nervous system and psychiatric disorders (e.g., sleep disorders, epilepsy and other convulsive disorders, anxiety, psychiatric diseases, neurodegenerative diseases, fever); 2. chronobiological-based disorders (e.g., jet lag, delayed sleep syndrome, shift-work, seasonal affective disorder); 3. endocrine indications (e.g., contraception and infertility, precocious puberty, premenstrual syndrome, hyperprolactinemia, growth hormone deficiency); 4. cancer and other proliferative diseases; 5. immune system disorders and conditions associated with senescence; 6. ophthalmological diseases; 7. animal breeding (e.g., regulation of fertility, puberty, pelage color).

Claims

1. A compound of the following formula ##STR83## wherein:

R¹, R², R³ and R⁴ are independently hydrogen, halogen, hydroxy, alkoxy or alkyaryl;

R⁵ is hydrogen, alkyl, alkylaryl or acetyl;

R⁶ is hydrogen, alkyl, alkylaryl or halogen;

n is 0 to 2;

m is 1 to 2;

R⁷ is --NHR⁸, ##STR84## l is 0 to 2;

R⁸ is hydrogen, ##STR85## or R⁹ ;

R⁹ is alkylene, aryl, alkylaryl, alkylcycloalkyl, ##STR86## R¹⁰ is cycloalkyl, CF₃, CH₃, ##STR87## R¹¹ and R¹² are hydrogen; and

R¹³ is alkyoxy, hydroxy, hydrogen, thioalkyl, alkylcycloalkyl or ##STR88## n'"'"' is 0 to 2;

with the proviso that if R⁶ is hydrogen, R⁷ is --NHR⁸ and

R⁸ is ##STR89## then R¹³ is not hydrogen;

if n is 2, then R¹⁰ is not cycloalkyl, CF₃ or ##STR90## where n'"'"' is 1 to 2;

if m is 1, R⁹ is not alkylene.

2. A compound of claim 1 having the following formula:

##STR91## wherein;

R¹, R², R³ and R⁴ are independently hydrogen, halogen hydroxy or alkoxy;

R⁵ is hydrogen;

R⁶ is hydrogen or halogen;

x is 0 or 1;

R¹¹ and R¹² are independently hydrogen, --NO₂, alkoxy, CF₃, alkyl, halogen or R¹¹ taken together with R¹² is ##STR92## and R¹³ is hydrogen, thioalkyl, alkylcycloalkyl or ##STR93## with the proviso that if R⁶ is hydrogen, R¹³ is not hydrogen.

3. A compound of claim 1 having the following formula:

##STR94## wherein R¹, R², R³ and R⁴ are independently hydrogen or alkoxy;

R⁵ is hydrogen;

R⁶ is hydrogen;

R¹⁰ is ##STR95## R¹¹ and R¹² are hydrogen; and

R¹³ is alkoxy or hydroxy.

5. A method of treating mammals for sleep disorders which method comprises administering a therapeutically effective amount of a compound of claim 1.

6. A method of treating mammals for sleep disorders which method comprises administering a therapeutically effective amount of a compound of claim 2.

7. A method of treating mammals for sleep disorders which method comprises administering a therapeutically effective amount of a compound of claim 3.

9. A pharmaceutical composition useful for treating sleep disorders which composition comprises a therapeutically effective amount of a compound of claim 1.

10. A pharmaceutical composition useful for treating sleep disorders which composition comprises a therapeutically effective amount of a compound of claim 2.

11. A pharmaceutical composition useful for treating sleep disorders which composition comprises a therapeutically effective amount of a compound of claim 3.

13. A compound of claim 1 which is N-Benzyloxycarbonyl)-5-fluorotryptamine.

14. A method of treating mammals for sleep disorders which method comprises administering a therapeutically effective amount a compound of claim 13.

15. A pharmaceutical composition useful for treating sleep disorders which composition comprises a therapeutically effective amount of a compound of claim 13.

4. A compound which is:

N-(p-Methoxybenzyloxycarbonyl)tryptamine;

N-(Benzyloxycarbonyl)-5-methoxytryptamine;

N-(p-methoxybenzyloxycarbonyl)-5-methoxytryptamine;

N-(Benzyloxycarbonyl)-5-hydroxytryptamine;

N-(Benzyloxycarbonyl)-5-fluorotryptamine;

3-(5-tetrazolyl)indole;

1-benzyl-3-(1-benzyl-5-tetrazolyl)indole;

1-benzyl-3-(2-benzyl-5-tetrazolyl)indole;

1-benzyl-3-(5-tetrazolyl)indole;

1-benzyl-3-[5-2-methyl-1,3,4-oxadiazolyl)indole;

N-(Benzyloxycarbonyl)-6-fluorotryptamine;

N-(p-methoxybenzyloxycarbonyl)-5-fluorotryptamine;

N-(4-Fluorobenzyloxycarbonyl)-5-fluorotryptamine;

1-acetyl-3-[5-2-methyl-1,3,4 oxadiazolyl)indole;

N-(Benzyloxycarbonyl)-5-chlorotryptamine;

N-(p-Chlorobenzyloxycarbonyl)tryptamine;

(p-Methylbenzyloxycarbonyl)tryptamine;

N-(p-Isopropylbenzyloxycarbonyl)tryptamine;

N-(3,4-Dimethylbenzyloxycarbonyl)tryptamine;

N-(p-Trifluoromethylbenzyloxycarbonyl)tryptamine;

N-(p-Nitrobenzyloxycarbonyl)-5-fluorotryptamine;

N-(3,4-methylenedioxybenzyloxycarbonyl)tryptamine;

N-[(S)-α

-Methylbenzyloxycarbonyl]tryptamine;

N-Cyclopropanemethyloxycarbonyl)-5-methoxytryptamine;

N[(R)-α

-methylbenzyloxycarbonyl]tryptamine;

2-Bromo-N-(Benzyloxycarbonyl)tryptamine;

N-[(S)-(-)-1,4-(nitrophenyl)-2-pyrrolidinemethyloxycarbonyl]tryptamine;

N-Cyclopentylmethyloxycarbonyl-5-fluorotryptamine;

N-Cyclobutylmethyloxycarbonyl-5-fluorotryptamine;

N-(Benzenesulfonyl)tryptamine;

N-(1-(R)-Methoxy-1-phenylacetyl)tryptamine;

N-(1-(S)-Methoxy-1-phenylacetyl)tryptamine;

N-Cyclopropylmethyloxycarbonyltryptamine;

2-Bromo-N-cyclopropylmethyloxycarbonyltryptamine;

2-Bromo-5-fluoro-N-benzyloxycarbonyltryptamine;

2-benzyltryptamine;

N-[(S)-mandeloyl]tryptamine;

N-[(R)-mandeloyl]tryptamine;

2-benzyl-5-methoxytryptamine;

1-[5-Fluoro-3-(2'"'"'-ethyl)indolyl]-3-benzylurea;

Di-[N-(methyleneoxycarbonyl)-tryptamine]-1,4-cis-cyclohexane;

or

di-[N-(methyleneoxycarbonyl)-tryptamine]-N-octane.

8. A method of treating mammals for sleep disorders which method comprises administering a therapeutically effective amount of a compound of claim 4.

12. A pharmaceutical composition useful for treating system sleep disorders which composition comprises a therapeutically effective amount of a compound of claim 4.

16. A method of treating mammals for sleep disorders which method comprises administering a therapeutically effective amount of a compound of selected from the group consisting of N-(Indole-3-actoyl)D-phenylanine, N-(Indole-3-acetoyl)benzylamine and N-(Indole-3-acetoyl)aniline.

17. A pharmaceutical composition useful for treating sleep disorders which composition comprises a therapeutically selective amount of a compound of selected from the group consisting of N-(Indole-3-acetoyl)D-phenylanine, N-(Indole-3-acetoyl)benzylamine and N-(Indole-3-acetoyl)aniline.