US3646053A - Certain-(2-amino-4-thiazolyl)indoles - Google Patents
Certain-(2-amino-4-thiazolyl)indoles Download PDFInfo
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- US3646053A US3646053A US38551A US3646053DA US3646053A US 3646053 A US3646053 A US 3646053A US 38551 A US38551 A US 38551A US 3646053D A US3646053D A US 3646053DA US 3646053 A US3646053 A US 3646053A
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- Prior art keywords
- amino
- thiazolyl
- indoles
- indole
- certain
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Definitions
- R is hydrogen or lower alkoxy.
- Suitable lower alkoxy groups contemplated by the present invention are those having up to four carbon atoms such as, for example, methoxy, ethoxy, n-propoxy, isobutoxy, etc.
- novel 3-(2-amino-4-thiazoyl)indoles of the present invention are, in general, white to yellow crystalline solids having characteristic melting points and absorption spectra. They are relatively insoluble in water, benzene, toluene, diethyl ether and petroleum ether but are relatively soluble in methanol, ethanol, ethyl acetate, dimethylformamide, and the like.
- the infrared and ultraviolet absorption spectra are characteristic of the novel compounds of the present invention and provide a preferred means of distinguishing and identifying them.
- novel compounds of the present invention are capable of forming pharmaceutically acceptable acid-addition salts with a variety of organic and inorganic acids.
- Such salts may be readily prepared by the simple addition of acid to the 3-(2-amino-4-thiazolyl)indole in an inert organic solvent such as methanol or ethanol.
- These salts include those prepared from acids such as hydrochloric, hydrobromic, hydriodic, sulfuric, phosphoric, sulfamic, tartaric, glycolic, citric, maleic, succinic, acetic, ascorbic, and the like.
- the free bases are equivalent to their non-toxic acid-addition sa ts.
- novel compounds of the present invention are active analgesics when measured by the writhing syndrome test for analgesic activity as described by Siegmund et al., Proc. Soc. Expt. Biol. Med., vol. 95, p. 729 (1957), with modifications.
- This method is based upon the reduction of the number of writhes following the intraperitoneal injection (if one mg./kg. of body weight of phenyl-p-quinone in male Swiss albino mice weighing -25 grams per mouse.
- the syndrome is characterized by intermittent confractions of the abdomen, twisting and turning of the trunk, and extension of the hind legs begining 3 to 5 minutes after injection of the phenyl-p-quinone.
- a compound is considered active if it reduces the total number of writhes in two test mice from a control value of approximately 30 per pair to a value of 18 or less per pair (counted for a 3 minute period of time commencing 15 minutes after injection). If desired, the results of this test procedure for 10 pairs of mice at each of several dose levels may be used to determine a median effective dose (ED defined as the dose required to reduce the number of writhes from about 30 per pair to 18 or less per pair in 50% of the pairs.
- ED median effective dose
- the following compounds of the present invention are active analgesics when tested in this procedure at the indicated oral dose as set forth in Table I below:
- novel compounds of the present invention may be administered either as the free base or as a non-toxic acidaddition salt thereof.
- the compounds may be administered orally or parenterally, if desired, and when so administered are active analgesics at individual doses ranging from about 1 to about 100 milligrams per kilogram of body weight.
- the dosage level can be adjusted to provide optimum therapeutic response. Thus, for example, several doses may be administered daily or the doses may be reduced proportionately as required.
- the active compounds of this invention may be incorporated with excipients and used, for example, in the form of tablets, pills, capsules, elixirs, suspensions, syrups and the like.
- Such preparations should contain at least 0.1% of active compound.
- the percentage of active compound in such preparations may, of course, be varied and may conveniently be between about 5% to about or more of the weight of the dosage unit.
- the amount of active compound in such therapeutically useful comopsitions is such that a suitable dosage level will be obtained.
- Preferred compositions according to the present invention are prepared so that a dosage unit form contains between about 10 and about 200 milligrams of active compound.
- the tablets, pills, capsules and the like may contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; a distintegrating agent such as a corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose or saccharin may be added or a flavoring agent such as peppermint, oil of Wintergreen or cherry flavoring.
- a binder such as gum tragacanth, acacia, corn starch or gelatin
- a distintegrating agent such as a corn starch, potato starch, alginic acid and the like
- a lubricant such as magnesium stearate
- a sweetening agent such as sucrose or saccharin may be added or a flavoring agent such as peppermint, oil of Wintergreen or cherry flavoring.
- a syrup, sus ension or elixir may contain the active compounds in the form of their non-toxic acid-addition salts, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
- novel 3-(2-amino-4-thiazolyl)indole derivatives of the present invention may be readily prepared by treating a 3-(haloacetyl)indole or a S-(lower alkoxy)-3-(haloacetyl)indole with thiourea in ethanol at reflux temperature for a period of time of about 1-2 hours. Concentration and dilution of the reaction mixtures with water induces crystallization of the products as white solids which may be removed by filtration.
- R is hydrogen; 3-(2-amino-4-thiazolyl)indole.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
THIS DISCLOSURE DESCRIBES COMPOUNDS OF THE CLASS OF 3-(2-AMINO-4-THIAZOLYL) INDOLES USEFUL AS ANALGESIC AGENTS.
Description
United States Patent O Ser. No. 38,551
Int. Cl. C07d 99/06 US. Cl. 260306.8 R Claims ABSTRACT OF THE DISCLOSURE This disclosure describes compounds of the class of 3-(2-amino-4-thiazolyl)indoles useful as analgesic agents.
CROSS REFERENCE TO RELATED APPLICATION This application is a continuation-in-part of our copending application Ser. No. 632,556, filed Apr. 21, 1967, now abandoned.
BRIEF SUMMARY OF THE INVENTION This invention relates to new derivatives of indole and, more particularly, is concerned with novel compounds which may be represented by the following general formula:
wherein R is hydrogen or lower alkoxy. Suitable lower alkoxy groups contemplated by the present invention are those having up to four carbon atoms such as, for example, methoxy, ethoxy, n-propoxy, isobutoxy, etc.
DETAILED DESCRIPTION OF THE INVENTION The novel 3-(2-amino-4-thiazoyl)indoles of the present invention are, in general, white to yellow crystalline solids having characteristic melting points and absorption spectra. They are relatively insoluble in water, benzene, toluene, diethyl ether and petroleum ether but are relatively soluble in methanol, ethanol, ethyl acetate, dimethylformamide, and the like. The infrared and ultraviolet absorption spectra are characteristic of the novel compounds of the present invention and provide a preferred means of distinguishing and identifying them.
The novel compounds of the present invention are capable of forming pharmaceutically acceptable acid-addition salts with a variety of organic and inorganic acids. Such salts may be readily prepared by the simple addition of acid to the 3-(2-amino-4-thiazolyl)indole in an inert organic solvent such as methanol or ethanol. These salts include those prepared from acids such as hydrochloric, hydrobromic, hydriodic, sulfuric, phosphoric, sulfamic, tartaric, glycolic, citric, maleic, succinic, acetic, ascorbic, and the like. For purposes of this invention, the free bases are equivalent to their non-toxic acid-addition sa ts.
The novel compounds of the present invention are active analgesics when measured by the writhing syndrome test for analgesic activity as described by Siegmund et al., Proc. Soc. Expt. Biol. Med., vol. 95, p. 729 (1957), with modifications. This method is based upon the reduction of the number of writhes following the intraperitoneal injection (if one mg./kg. of body weight of phenyl-p-quinone in male Swiss albino mice weighing -25 grams per mouse. The syndrome is characterized by intermittent confractions of the abdomen, twisting and turning of the trunk, and extension of the hind legs begining 3 to 5 minutes after injection of the phenyl-p-quinone. A compound is considered active if it reduces the total number of writhes in two test mice from a control value of approximately 30 per pair to a value of 18 or less per pair (counted for a 3 minute period of time commencing 15 minutes after injection). If desired, the results of this test procedure for 10 pairs of mice at each of several dose levels may be used to determine a median effective dose (ED defined as the dose required to reduce the number of writhes from about 30 per pair to 18 or less per pair in 50% of the pairs. In a representative operation, and merely by way of illustration, the following compounds of the present invention are active analgesics when tested in this procedure at the indicated oral dose as set forth in Table I below:
TABLE I Oral dose, mg/kg. Compound: of body weight 3-(2-amino-4-thiazolyl)indole 50 3-(2-amino-4-thiazolyl)-5-methoxyindole 100 In addition, supplementary test procedures such as measuring the elevation of the pain threshold of rat paws inflamed with brewers yeast may be carried out to confirm the analgesic activity of these compounds.
The novel compounds of the present invention may be administered either as the free base or as a non-toxic acidaddition salt thereof. The compounds may be administered orally or parenterally, if desired, and when so administered are active analgesics at individual doses ranging from about 1 to about 100 milligrams per kilogram of body weight. The dosage level can be adjusted to provide optimum therapeutic response. Thus, for example, several doses may be administered daily or the doses may be reduced proportionately as required.
For therapeutic administration, the active compounds of this invention may be incorporated with excipients and used, for example, in the form of tablets, pills, capsules, elixirs, suspensions, syrups and the like. Such preparations should contain at least 0.1% of active compound. The percentage of active compound in such preparations may, of course, be varied and may conveniently be between about 5% to about or more of the weight of the dosage unit. The amount of active compound in such therapeutically useful comopsitions is such that a suitable dosage level will be obtained. Preferred compositions according to the present invention are prepared so that a dosage unit form contains between about 10 and about 200 milligrams of active compound.
The tablets, pills, capsules and the like may contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; a distintegrating agent such as a corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose or saccharin may be added or a flavoring agent such as peppermint, oil of Wintergreen or cherry flavoring. A syrup, sus ension or elixir may contain the active compounds in the form of their non-toxic acid-addition salts, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
The novel 3-(2-amino-4-thiazolyl)indole derivatives of the present invention may be readily prepared by treating a 3-(haloacetyl)indole or a S-(lower alkoxy)-3-(haloacetyl)indole with thiourea in ethanol at reflux temperature for a period of time of about 1-2 hours. Concentration and dilution of the reaction mixtures with water induces crystallization of the products as white solids which may be removed by filtration.
3 The following examples are given solely for the purpose of illustration and are not to be construed as limitations of this invention, many apparent variations of which are possible without departing from the spirit or scope thereof.
EXAMPLE 1 3- 2-amino-4-thiazolyl) indole A magnetically stirred mixture of 476 mg. (2 mmoles) of 3-(bromoacetyl)indole [G, Sauna, Gazz. chi'm. ital. 57, 169 (1929)], 304 mg. (4 mmoles) of thiourea, and 0.55 ml. of triethylamine in 40 ml. of ethanol was heated at reflux for 2 hours. After partial removal of solvent, water was added and the concentrate was cooled to give 349 mg. of tan solid. Recrystallization from ether-petroleum ether gave a white solid, M.P. l66-l68 C.
EXAMPLE 2 3-(chloroacetyl)-5-methoxyindole Chloroacetyl chloride (5.27 ml., 0.070 mole) in anhydrous ether (20 ml.) was added dropwise to an icecooled ether solution of iodo magnesylindole, prepared by treating S-methoxyindole (10.0 g., 0.068 mole) with methylmagnesium iodide, obtained from 1.63 g. (0.068 mole) of magnesium and 10 g. (0.071 mole) of methyl iodide. The reaction mixture then was magnetically stirred for 4 hours in an ice bath. Ice was added to the solution with vigorous stirring and the solid filtered and Washed well with ether. The solid was recrystallized from methanol to give 2.724 g. of pink solid, M.P. 2l2-2l4 C.
EXAMPLE 3 3- (2-amino-4-thiazolyl -5-n1ethoxyindole Treatment of 3-(chloroacetyl)-5-methoxyind0le (Exam- 4 pie 2) (1.427 g.) with thiourea (920 mg.) by the procedue of Example 1 gave after recrystallization from methanol, 1.138 g. (67%) of crystals, M.P. ISO-182 C.
What is claimed is: 1. A compound selected from the group consisting of those of the formula:
I l N y H NH wherein R is selected from the group consisting of hydrogen and lower alkoxy; and the pharmaceutically acceptable acid-addition salts thereof.
2. A compound according to claim 1 wherein R is hydrogen; 3-(2-amino-4-thiazolyl)indole.
3. A compound according to claim 1 wherein R is methoxy; 3- 2-amino-4-thiazolyl) -S-methoxyindo1e.
4. A compound according to claim 1 wherein R is ethoxy; 3- (2-amino-4-thiazolyl -5-ethoxyindole.
5. A compound according to claim 1 wherein R is isopropoxy; 3- 2-amino-4-thiazolyl -5-isopropoxyindole.
References Cited Sadeh et al., Israel J. Chem., 4 (la), 24 p (October 1966).
ALEX MAZEL, Primary Examiner R. J. GALLAGHER, Assistant Examiner US. Cl. X.R. 424-200, 270
Applications Claiming Priority (1)
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US3855170A | 1970-05-18 | 1970-05-18 |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0328200A1 (en) * | 1988-02-12 | 1989-08-16 | Merck Sharp & Dohme Ltd. | Five-membered ring systems with bonded azacyclic ring substituents |
US4940703A (en) * | 1988-04-11 | 1990-07-10 | Merck Sharp & Dohme Limited | Spirocyclic compounds incorporating five-membered rings with two heteroatoms for treating psychotic disorders, etc. |
-
1970
- 1970-05-18 US US38551A patent/US3646053A/en not_active Expired - Lifetime
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0328200A1 (en) * | 1988-02-12 | 1989-08-16 | Merck Sharp & Dohme Ltd. | Five-membered ring systems with bonded azacyclic ring substituents |
JPH01268687A (en) * | 1988-02-12 | 1989-10-26 | Merck Sharp & Dohme Ltd | 5-membered ring system of azacyclic substituent bond |
US4952587A (en) * | 1988-02-12 | 1990-08-28 | Merck Sharp & Dohme Ltd. | Physiologically active 1,2,4,-oxa- and thiadiazoles |
AU614027B2 (en) * | 1988-02-12 | 1991-08-15 | Merck Sharp & Dohme Limited | Five-membered ring systems with bonded azacyclic ring substituents |
JP2505875B2 (en) | 1988-02-12 | 1996-06-12 | メルク シヤープ エンド ドーム リミテツド | 5-membered ring system with azacyclic substituent bond |
US4940703A (en) * | 1988-04-11 | 1990-07-10 | Merck Sharp & Dohme Limited | Spirocyclic compounds incorporating five-membered rings with two heteroatoms for treating psychotic disorders, etc. |
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