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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- Expired - Lifetime
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- 150000002475 indoles Chemical class 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 abstract description 23
- 239000000730 antalgic agent Substances 0.000 abstract description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- -1 for example Chemical group 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 6
- ZACIGHHWMWRYSZ-UHFFFAOYSA-N 4-(1h-indol-3-yl)-1,3-thiazol-2-amine Chemical class S1C(N)=NC(C=2C3=CC=CC=C3NC=2)=C1 ZACIGHHWMWRYSZ-UHFFFAOYSA-N 0.000 description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 229940035676 analgesics Drugs 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 3
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- RLQZIECDMISZHS-UHFFFAOYSA-N 2-phenylcyclohexa-2,5-diene-1,4-dione Chemical compound O=C1C=CC(=O)C(C=2C=CC=CC=2)=C1 RLQZIECDMISZHS-UHFFFAOYSA-N 0.000 description 2
- 241000167854 Bourreria succulenta Species 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 235000019693 cherries Nutrition 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- WCDLGQZBYNBTFK-UHFFFAOYSA-N 2-bromo-1-(1h-indol-3-yl)ethanone Chemical compound C1=CC=C2C(C(=O)CBr)=CNC2=C1 WCDLGQZBYNBTFK-UHFFFAOYSA-N 0.000 description 1
- DSMFLFNPUPWNQN-UHFFFAOYSA-N 4-(5-methoxy-1h-indol-3-yl)-1,3-thiazol-2-amine Chemical compound C12=CC(OC)=CC=C2NC=C1C1=CSC(N)=N1 DSMFLFNPUPWNQN-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 244000246386 Mentha pulegium Species 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- 235000004357 Mentha x piperita Nutrition 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 208000000114 Pain Threshold Diseases 0.000 description 1
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000007958 cherry flavor Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VXWPONVCMVLXBW-UHFFFAOYSA-M magnesium;carbanide;iodide Chemical compound [CH3-].[Mg+2].[I-] VXWPONVCMVLXBW-UHFFFAOYSA-M 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000007968 orange flavor Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000037040 pain threshold Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
Classifications
-
- 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.
Landscapes
- 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)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US3855170A | 1970-05-18 | 1970-05-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3646053A true US3646053A (en) | 1972-02-29 |
Family
ID=21900580
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US38551A Expired - Lifetime US3646053A (en) | 1970-05-18 | 1970-05-18 | Certain-(2-amino-4-thiazolyl)indoles |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | US3646053A (en) |
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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