AP388A - Inhibition of the replicateion of HIV and related viruses using thiourea derivative compounds or salts thereof. - Google Patents

Inhibition of the replicateion of HIV and related viruses using thiourea derivative compounds or salts thereof. Download PDF

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Publication number
AP388A
AP388A APAP/P/1995/000723A AP9500723A AP388A AP 388 A AP388 A AP 388A AP 9500723 A AP9500723 A AP 9500723A AP 388 A AP388 A AP 388A
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ARIPO
Prior art keywords
pyridyl
thiourea
substituted
ethyl
mmol
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APAP/P/1995/000723A
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AP9500723A0 (en
Inventor
Peter Thomas Lind
Jr John Michael Morin
Rolf Noreen
Robert John Ternansky
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Medivir Ab
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Publication of AP9500723A0 publication Critical patent/AP9500723A0/en
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Publication of AP388A publication Critical patent/AP388A/en

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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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    • C07D213/72—Nitrogen atoms
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    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
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    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/20—Nitrogen atoms
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    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/14—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C07D257/06—Five-membered rings with nitrogen atoms directly attached to the ring carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/48—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
    • C07D275/03—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/18—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/48—Acylated amino or imino radicals by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof, e.g. carbonylguanidines
    • C—CHEMISTRY; METALLURGY
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    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/82—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C07D285/135—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • 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
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    • C07D417/12—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 linked by a chain containing hetero atoms as chain links

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Abstract

Method for inhibiting the replication of hiv by contacting hiv with a compound of the formula:

Description

R,« is (a), a stable 3 to 8 monocyclic ring having 0 to 4 hetero atoms selected from S, 0 and N (b) a stable 7 to 10 bicyclic ring having 0 to 5 hetero atoms selected from S, 0 and N (c) (Rio)<X wherein : y is 1 or 2
X is S, 0 or M
R10 is either R,4(a) or (b) (d) H, -CN, -COOH, -N<, -COSH, -OH or C,-C* alkyl (e) halo, C,-C4 alkoxy, Cj-C, alkenyl, alkynyl or alkenoxy
Rl2, Ri3 and Ru are independently (a) the same as Rl4(d) (b) -CHjOH,-CHjNH2, -CH2C00H, Cj-C4 alkenyl, -NOj, C,-C4 alkanoyloxy, C,-C4 alkylthio, carbamoyl or halo substituted (C,-CJ alkyl
Ri3 is R14(a) or (b), or R„
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A feature of this invention also disclosed is a method of administering to a human in need thereof the compounds of the invention or their pharmaceutically acceptable salts to treat or inhibit HIV/AIDS, to inhibit the replication of the HIV/AIDS virus in infected human cells and to inhibit AIDS from developing in humans infected with the HIV/AIDS virus or carrying antibodies to the HIV/AIDS virus.
The present invention also discloses the 13 compounds of the invention and their salts for use in the treatment of the condition referred to above, as well as the use of such compounds in the preparation of pharmaceutical formulations for the treatment cf such conditions.
In general for the treatment as described above, a suitable effective dose of the compound or its pharmaceutically acceptable salt will be in the range of 0.5 to 250 mg per kilogram bodyweight of recipient per day. Administration may be by any suitable route including oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. It will be appreciated that the preferred route may vary with, for example, the condition, age, and weight of the recipient.
The administered ingredients may be used as a therapy in conjunction with other therapeutic agents, (other ar.ti-virals, anti-bacterials, compounds useful for preventing resulting secondary or contemporaneous afflictions associated with HIV/AIDS) such as AZT, ddl, ddC, 9-[[2-hydroxy-l-(hydroxymethyl)ethoxy)methyl]guanine,
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ΑΡθ ύ Ο 3 8 8
- 3 9-(2-hydrcxyethoxymethyl)guanine(acyclovir), 2-amino-9-(2hydrcxyethcxymethyl) purine, suramin, ribavarin, antimoniotungstate (HPA-23), interferon, e.g., a interferon, interleukin II, and phosphonoformate (Foscarnet) or in conjunction with other immune modulators including bone marrow or lymphocyte transplants or other medications such as levamisol or thymosin which would increase lymphocyte numbers and/or function as is appropriate .
For example, in an evaluation of the combination of AZT and a compound of the formula
Η K a synergistic effect was observed. The combination was evaluated against HIV-1 in CEM cells using the technique of Prichard and Shipman (Antiviral Research, 14, 181-206 (1990)). The peak of synergy was observed at 0.5 pg/ml of the compound of the formula above and 0.005 gg/ml of AZT.
While it is possible for the administered ingredients to be administered alone, it is preferable to present them as part of a pharmaceutical formulation. The formulations of the present invention comprise at least one administered ingredient, as above-defined together with or.e or more acceptable carriers thereof and optionally other therapeutic ingredients. The carrier(s) must be •acceptable in the sense of being compatible with the_ £ '0 ZOO / 56 /d/dV
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AP Ο Ο Ο 3 8 8 other ingredients of the formulation and not deleterious to the recipient thereof.
The formulations include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. The formulations may conveniently be presented in unit dosage form, e.g., tablets and sustained release capsules, and may be prepared by any methods well known in the art of pharmacy.
Such methods include the step of bringing into association the to be administered ingredients with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion and as a bolus, etc.
With regard to compositions for oral administration (e.g. tablets and capsules), the term 'suitable vehicle means common excipients such as binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidine (Povidone),
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- 5 methylcellulose, ethylcellulose, sodium carboxymethylceliulose, hydroxypropylmethylcellulose, sucrose and starch; fillers and carriers, for example corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid; disintegrators such as microcrystalline cellulose, com starch, sodium starch glycolate, alginic acid; and lubricants such as magnesium stearate and other metallic stearates, stearic acid, silicone fluid, talc, waxes, oils and colloidal silica. Flavoring agents such as peppermint, oil of Wintergreen, cherry flavoring or the like can also be used. It may be desirable to add a coloring agent to make the dosage form more aesthetically pleasing in appearance or to help identify the product.
The tablets may also be coated by methods well known in the art.
A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfaceactive or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
Formulations suitable for topical administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; pastilles
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APO00388
comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the ingredient to be administered in a suitable liquid carrier.
Formulations suitable for topical administration to the skin may be presented as ointments, creams, gels and pastes comprising the ingredient to be administered and a pharmaceutically acceptable carrier. An exemplary topical delivery system is a transdermal patch containing the ingredient to be administered.
Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.
Formulations suitable for nasal administration 15 wherein the carrier is a solid include a coarse powder having a particle size, for example, in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable formulations wherein the carrier is a liquid, for administration, as for example, a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient.
Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
Formulations suitable for parenteral administration include aqueous and non-aqueous sterile
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- Ί buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
The formulations may be presented in unit-dose or multidose containers, for example, sealed ampules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, or example water for injections, immediately prior to use.
Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the kind previously described.
Preferred unit dosage formulations are those containing a daily dose or unit, daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the administered ingredient.
The antiviral compounds of Formula I can be used as surface disinfectants. Solutions containing as little as 0.1 percent by weight of the antiviral compound maybe effective for disinfecting purposes. Preferably, such solutions also can contain a detergent or other cleansing agent. The solutions maybe useful for disinfecting objects such as glassware, dental and surgical instruments, and surfaces such as walls, floors, and tables in areas where maintenance of sterile conditions is important, for example., hospitals, food-preparation areas, and the like.
In practicing the method for treating or inhibiting HIV and/or AIDS, the antiviral can be administered in a single daily dose or in multiple doses per day. The treatment regime may require administration £ ?. L 0 0 / C 6 -/d/dV
AP Ο Ο Ο 3 8 8
- 8 for several months or years. The amount administered per dose or the total amount administered will depend on such factors as the nature and severity of the infection, the age and general health of the patient, the tolerance of both the patient and the microorganism or microorganisms involved in the infection to the antiviral compound.
The following formulation examples represent specific pharmaceutical formulations employing compounds comprehended by the present method. The formulations may employ as active compounds any of the compounds of Formula I or a pharmaceutically acceptable salt thereof. The examples are illustrative only and are not intended to limit the scope of the invention in any way.
fggBULa&iPn 1
Hard gelatin capsules are prepared using the following ingredients:
Quantity JEiaZ-caBsuIgl
Compound
Starch dried Magnesium stearate
1250
200
The above ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities.
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- 9 Formulation 2
A tablet formula is prepared using the ingredients below:
Quantity, (ipq/tablet!
Compound 250
Cellulose, microcrystalline 400
Silicon dioxide, fumed 10
Stearic acid 5
Magnesium stearate 10
The components are blended and compressed to form tablets each weighing 675 mg.
Formulation 3
An aerosol solution is prepared containing the 15 following components:
Meiaht
Compound 0.25
Ethanol 29.75
Propellant 22 70.00 (Chlorodifluoromethane)
The active compound is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to -30eC and transferred to a filling device. The required amount is then placed in a stainless steel container and diluted with the remainder of the propellant. The valve units are then fitted to the container.
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- 10— formulation 4
Tablets each containing 60 mg of active ingredient are made up as follows:
Compound 60 mg
Starch 45 mg
Microcrystalline cellulose 35 mg
Polyvinylpyrrolidone (as 10% solution in water) 4 mg
Sodium carboxymethyl starch 4.5 mg
Magnesium stearate 0.5 mg
Talc 1 mg
The active ingredient, starch and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 40°-6Q°C and passed through a No. 18 mesh U.S. sieve.
The sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
Formulation 5
Capsules each containing 80 mg of medicament are made as follows:
AP/P/ 95/00723
Compound 80 mg
Starch 59 mg
Microcrystalline cellulose 59 mg
Silicone fluid 2 mg
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- 11 The active ingredient, cellulose, starch and magnesium stearate are blended, passed through a No. 45 mesh U.S. sieve, and filled into hard gelatin capsules in 200 mg quantities.
EoirmlaEipn.fi
Suppositories each containing 225 mg of medicament are made as follows:
Compound 225 mg
Saturated fatty acid glycerides 2 mg
The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool.
Formulation 7
As intravenous formulation is prepared as follows:
Compound 100 mg
Isotonic saline 1000 ml
The solution of the above ingredients is administered intravenously at a rate of 1 ml/minute to a mammal in need of treatment.
It should be understood that in addition to the ingredients particularly mentioned above the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question.
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- 12 The following examples further illustrate the compounds of the present invention and methods for the synthesis. The examples are not intended to be limiting to the scope of the invention in any respect and should not be so construed.
Exaripies,, and fEBBedures
The following are experimentals illustrating methods for preparing the compounds of the invention.
Eaawla ..1
N-(2-Phenethvl)-Ν'-f2-(1,3,4-thiadiazolvl?1 thiourea
A solution of 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) and 2-amino-l,3,4-thiadiazole (2.02 g, 20 mmol) in N,N-dimethylformamide (50 mL) was heated to 100eC. After 68 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid, saturated sodium bicarbonate solution, and water. The organic layer was filtered and the solid obtained (2.24 g) triturated with ethyl acetate to provide 1.9 g (36%) of the title
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AP Ο Ο Ο 3 β 8
- 13 mp 210-211.5°C;
IR (KBr, cm1) 3320, 2924, 2869, 2685, 1645, 1543, 1453, 1384, 1344, 1278, 762, 749, 700, 650;
:H NMR (300 MHz, DMSO-cfg) δ 12.35 (br s, IH), 8.92 (s, IH) , 5 8.78 (br s, IH), 7.38-7.18 (m, 5H), 3.84-3.72 (m, 2H), 2.92 (t, J=6 Hz, 2H);
MS (FD) m/e 264 (M+);
UV (EtOH) 277nm, 253nm, 205nm.
Anal. Calcd for C11H12N4S2:
Theory; C, 49.98; H, 4.57; n, 21.19.
Found; C, 50.07; H, 4.66; N, 21.48.
Example 2
N-.L2-Phenethyl) -Ν' -f4,5-dimethvl- (2-thiazolvl) 1 thiourea
bO
CM r0 m
cn
E
E <
2-Amino-4,5-dimethylthiazole hydrochloride (3.3 g, 20 mmol) was slurried with methylene chloride and shaken with saturated sodium bicarbonate solution. The layers were separated and the aqueous washed with methylene chloride (2x). The combined organics were dried over magnesium sulfate, filtered and concentrated. To the resulting solid was added 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) and JV, N-dimethylformamide (50 mL) . The resulting
APO.OO 3 88
- 15 was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid, saturated sodium bicarbonate solution, and water (2x). The organic layer was filtered and the solid obtained (3.9 g) recrystallized from ethyl acetate to provide 3.3 g (57%) of the title product:
mp 186-7°C;
IR (KBr, cm1) 3166, 3022, 1523, 1502, 1289, 1215, 737,
695;
1H NMR (300 MHz, DMSO-dg) 6 11.42 (br s, IH) , 9.83 (br s, IH), 7.36-7.16 (m, 5H), 3.86-3.73 (m, 2H), 2.91 (t, J=7 Hz, 2H), 2.19 (s, 3H), 2.08 (s, 3H) ;
MS (FD) m/e 291 (M+);
W (EtOH) 298nm (£=17987), 257nm {£=9939), 204nm (£=20802). Anal. Calcd for C14H17N3S2:
Theory: C. 57.70; H, 5.80; N, 14.42.
Found: C, 57.41; H, 5.85; N, 14.39.
E2SAISDie_i
N- f2- (4--Methvl) -l-Dhenethyl) -Ν' - (2-thiazolvl) thiourea
AP/P/ 9 5 / 0 0 7 2 3
A solution of 2-(4-methylphenethyl) isothiocyanate (820 mg, 4.6 mmol, and 2-aminothiazole (565 mg, 5.65 mmol) in Ν,Ν-dimethylformamide (15 mL) was heated BA0 ORIG>nal
AP Ο Ο Ο 3 8 8
- 16 to 1OO°C. After 20.5 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid (2x) , saturated sodium bicarbonate solution, and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The solid obtained (1.1 g) was purified ty flash chromatography on silica gel (1% ethyl acetate in methylene chloride) to provide 570 mg (45%) of the titled compound. A sample was recrystallized from ethyl acetate:
mp 132-3°C;
IR (KBr, cm-1) 3168, 2990, 1560, 1513, 1166, 808, 705;
Lh NMR (300 MHz, DMSO-£?6) δ 11.62 (br s, IH) , 9.69 (br s, IH). 7.36 (d, J=4 Hz, IH), 7.20-7.06 (m, 5H) , 3.83-3.73 (m, 2H), 2.87 (t, J=7 Hz, 2H), 2.30 (s, 3H);
MS (FD) m/e 277 (M+);
UV (EtOH) 288nm (£=18773), 257nm (£=11948), 212nm (e=14509).
Anal. Calcd for C13H15N3S2:
Theory: C, 56.29; H, 5.45; N, 15.15.
Found: C, 56.55; H, 5.52; N, 15.04.
AP/PZ 9 5 / 0 0 7 23
Example 4
N.-.12.T£>henethvl) -Ν' - (2-pvridvl) thiourea
APO 0 0 3 88
- 17 A solution of 2-phenethyl isothiocyanate (3.26 g, 21 mmol, 3.0 mL) and 2-aminopyridine (1.90 g, 20 mmol) in Λ',.ν-dimethylf ormamide (50 mL) was heated to 100°C. After
4 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic solution was washed with water (3x). The organic layer was dried over sodium sulfate, filtered and concentrated. The resulting white solid was recrystallized from ethyl acetate to provide 1.86 g ί36%) of the titled product: mp 153-154°C;
IR (K3r, cm1) 3232, 1536, 1477, 1319, 775;
Th NX?. (3CC MHz, CDCI3) δ 11.72 (br s, IH) , 8.59 (br s, IH), 7.97 (d, J=4.2 Hz, IH) , 7.64(dt, J = 1.7,8.2 Hz, IH),
7.37--.26 im, 5H) , 6.92 (dd, J=7.2,5.1 Hz, IH) , 6.74 (d,
J=8.2 Hz, IH), 4.06 (m, 0=6.8 Hz. 2H), 3.04 (t, J=6.9 Hz,
2H) ;
MS (FT) m/e 257 (M+);
UV (EtOH) 293nm (£=12040), 266nm (£=12961), 247nm (£=11912)
202nm (£=12963) .
Anal. Calcd for C14H15N3S:
Theory: C, 65.35; H, 5.87; N, 16.33.
APO 0 0 38 8
N- (2-phenethylJ -ILL- (4-Pvridvl) thiourea *1 · W
- 18 Example 5
A solution of 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) and 4-aminopyridine (1.92 g, 20 mmol) in N, W-dimethylformamide (50 mL) was heated to 100°C. After
4.5 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic solution was washed with water (2x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The oil obtained was purified by flash chromatography on silica gel (5% methanol in ethyl acetate to 10% methanol in ethyl acetate) . This material was recrystallized from ethyl acetate yielding 1.85g (36%) of the title product: mp 154.5°C;
IR (KBr, cm-1) 3142, 1579, 1518, 1328, 1276, 750;
iH NMR .(300 MHz, CDCI3) 5 8.42 (dd, J=l,5 Hz, 2h) , 7.94 (br s, IH), 7.39-7.23 (m, 5Η), 6.81 (d, J=5 Hz, 2H), 6.38 (br s, IH), 3.99 (m, J=6 Hz, 2H), 3.02 (t, J=6 Hz, 2H):
MS (FD) m/e 258 (M+l);
UV (EtOH) 281nm (£=16486), 255nm (£=21182), 208nm (£=25744). Anal. Calcd for C14H15N3S:
Theory: C, 65.34; H, 5.87; N, 16.33.
Found: C, 65.43; H, 5.97; N, 16.17.
AP/P/ 9 5 / 0 0 7 23
AP ο Ο Ο 3 8 8
- 19 Example 6
M-^-ohenethyDrN’-f2- (6-fluoro? -benzothiazolyl) thiourea
A solution of 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0mL) and 2-amino-6-fluoro-benzothiazole (3.36 , g, 20 mmol) in dimethylsulfoxide (10 mL) was heated to 10 150°C. After 5 h, the reaction was cooled to room temperature and filtered. The filtrate was poured into ethyl acetate, washed with water (5x) and brine (2x). The organic layer was concentrated and recrystallized from ethyl acetate to provide 729.5 mg (11%) of the titled product:
mp 212-213°C;
IR (KBr, cm’1) 3175, 3025, 1561, 1534, 1461, 1249, 1215;
1h NMR (300 MHz, CDC13) δ 11.81 (br s, IH) , 9.83 (br s,
IH), 7.77 (dd, J=8.7, 2.4 Hz, IH), 7.52 (br s, IH), 7.3120 7.15 (m, 6H), 3.79 (m, 2H), 2.90 (t, J=6.6 Hz, 2H);
MS (FD) m/e 331 (M+);
AP/P/ 9 5 / 0 0 7 2 3
AP Ο Ο Ο 3 8 8
- 20 Anal. Calcd for C16H14N3S2F:
Theory: C, 57.98; H, 4.26; N, 12.68.
Found: C, 57.74; H, 4.39; N, 12.53.
E2LaffiDl£_Z
N- (2-ohenethvl) -Ν' - f 2-, LA-phfiny-l_-5r tetradecvl) -thiazolvll
Lhiourga
A solution of 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3 mL) and 2-amino-4-phenyl-5-tetradecylthiazole (7.45 g, 20 mmol) in N,//-dimethyl formamide (50 mL) was heated to 100°C. After 24 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic solution was washed with IN hydrochloric acid, saturated sodium bicarbonate solution, water (3x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The material was recrystallized from ethyl acetate (once) and hexanes (once) to provide
4.93 g (46%) of the title product:
AP/P/ 9 5 / 0 0 7 2 3
APOOO 388
- 21 IR (KBr, cm-1) 3166, 3022, 2915, 1850, 1574, 1523, 1502, 1215, 695;
1H NMR (300 MHz, CDC13) 5 10.87 (br s, IH), 9.28 (br s, IH), 7.55-7.16 (m, 10H), 4.00-3.95 (m, 2H), 2.99 (c, J=7
Hz, 2H), 2.79 (t, J=9Hz, 2H), 1.65-1.00 (m, 24H), 0.86 (t, J=6 Hz, 3H);
MS (FD) m/e 535 (M+);
UV (EtOH) 299nm (£=19199), 261nm (£=17809), 203nm (£=31542) Anal. Calcd for C32H45N3S2:
Theory: C, 71.73; H, 8.46; N, 7.84.
Found: C, 71.93; H, 8.75; N, 7.92.
Example.. J
R?. 12^iroethoxy-L-Phenethyl 1.711(.- (2-thiazolvl) thiourea bO h3co, h3co' h3co, h3co'
CX ex
Η H
AP/P/ 9 5 / 0 0 7 2
A solution of 2-(3,4-dimethoxyphenethyl) isothio-cyanate (0.52 g, 2.33 mmol) and 2-aminothiazole (233 mg, 2.33 mmol) in Ν,Ν-dimethylformamide (10 mL) was heated to lOO’c. After 24 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic, solution was washed with IN hydrochloric acid, saturated sodium bicarbonate solution, water (3x) and
AP Ο Ο Ο 3 β β
- 22 brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The oil was recrystallized from toluene to provide 129mg (17%) of the title product: mp 139°C;
IR (KBr, αη'1) 3168, 3112, 3013, 1572, 1550, 1516, 1461.
1263, 1237, 1183;
ZH NMR (300 MHz, DMSO-d6) δ 11.55 (br s, IH) , 9.80-9.62 (br s, 1H', 7.35 (m, IH), 7.15 (br s, IH), 6.90-6.75 (m, 3H, , 3.80-3.70 (m, 2H), 3.72 (s, 6H), 2.84 (t, J=6 Hz, 2H);
MS (FD) m/e 323 (M+);
UV (EtOH) 287nm (£=21678), 258nm (£=11828), 228nm (£=11401), 205nm (£=36669).
Anal. Calcd for C14H17N3O2S2:
Theory: C, 51.99; H, 5.30; N, 12.99.
Found: C, 51.96; H, 5.51; N, 13.02.
£ Z L 0 0 / fc 6 /d/dV
BAD ORIGINAL $
AP Ο Ο Ο 3 β 8
U3
- 23 Example 9
Ν- (2-phenethyl)-Ν'-(2-(4-(4-bromoohenvl))thiazolyl1 thiourea
A solution of 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3 mL) and 2-amino-4- (4-bromophenyl) thiazole (5.15 g, 20 mmol) in N,N-dimethylformamide (50 mL) was heated to 100°C. After 65 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic solution was washed with IN hydrochloric acid, saturated sodium bicarbonate solution, water (3x) and brine. The organic layer contained as solid which was filtered. The filtrate was dried over sodium sulfate, filtered and concentrated and added to the filtered solid.
The combined material was recrystallized from ethyl acetate to provide 12.04 g (24%) of the title product:
mp 215.5-216.5°C;
IR (KBr, cm-1) 3166> 3022, 1574, 1523, 1502, 737, 695;
AP/P/ 95/00723
OrtGlNM- &
AP Ο Ο Ο 3 8 8
- 24 Ιη NMR (300 MHz, EMSO-d^) δ 11.70 (br s, ΙΗ), 9.40 (br s, IK) , 7.74-7.54 (m, 5Η) , 7.36-7.18 (m, 5Η) , 3.90-3.81 (m,
2Η), 2.96 (t, J=6 Hz, 2Η);
IIS (FD) m/e 419 (M+1);
UV (EtOH) 287nm (£=28740), 268nm (£=24574), 246nm (£=18009), 203nm (£=35813).
Anal. Calcd for Ci8H16N3S2Br:
Theory: C, 51.68; H, 3.86; N, 10.04.
Found: C, 51.39; H, 3.77; N, 9.77.
Example IQ ti.- Γ 2 7 (4 -Chloral TDheaethzl] -N' - (2 - thiazolyl) thiourea
A solution of 2-(4-chloro)-phenethyl isothiocyanate (657 mg, 3.3 mmol) and 2-aminothiazole (335 mg, 3.3 mmol) in Ν,Ν-dimethylformamide (10 mL) was heated to lOO’c. After 20.5 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic solution was washed with IN hydrochloric acid, saturated sodium bicarbonate solution, and water (3x). The organic
AP/P/ 9 5 / 0 0 7 2 3
APO 0 0 3 8 8
- 25 concentrated. The material was recrystallized from ethyl acetate (2x) to provide 136 mg (14%) of title product: mp 154-155°C;
IR (KBr, cm'1) 3090, 2991, 1561, 1515, 1490, 1176;
yH NMR .(300 MHz, DMSO-d6) δ 11.58 (br s, IH) , 9.78-9.60 (br s, IH), 7.40-7.28 (m, 5H), 7.12 (br s, IH), 3.81-3.72 (m, 2H), 2.92 (t, J=6 Hz, 2H);
MS (FD) m/e 297 (M+);
UV (EtOH) 289nm (£=19572), 257nm (£=12071), 220nm (£=15393), 1C 202nm (£=22079).
Anal. Calcd for C12H12N3S2CI:
Theory: C, 48.40; H, 4.06; N, 14.11.
Found: C, 48.17; H, 4.02; N,13.83.
Example 11
N.-.12-Phenethvli-N.! -J 2-1.4 ,.5-dihvdro) thiazolvll thiourea
H
AP/P/ 9 5/ 0 0 7 2 3 g, 10 mmol, 1.5 mL) and 2-amino-4,5-dihydrothiazole (1.02 g, 10 mmol) in dimethylsulfoxide (10 mL) was heated to 100 C. After 2.5 h, the reaction was cooled to room
ΒΑθ original
AP Ο Ο Ο 3 8 θ
- 26 temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid (2x), water (4x), and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was recrystallized from ethyl acetate to provide 1.48 g (56%) of title product as a white crystalline solid. A sample was recrystallized a second time from ethyl acetate: mp 132-134°C;
IR (KBr, cm-1) 3161, 3027, 2945, 2862, 1630, 1574, 1552, .0 1221, 1033;
!h NMR (300 MHZ, CDCI3) 6 11.11 (br s, IH), 8.36 (s, IH) ,
7.32-7.14 (m, 5H), 4.05-3.97 (m, 2H), 3.90-3.83 (m, 2H) ,
3.30-3.22 (m, 2H), 2.94 (t, J=7.1 Hz, 2H);
MS (El) m/e 265 (M+);
UV (EtOH) 269nm (£=18349), 206nm (£=18745).
Anal. Calcd for C12H15N3S2:
Theory: C, 54.31; H, 5.70; N, 15.83.
Found: C, 54.36; H, 5.66; N, 15.78.
Example 12
M-J.2tPhenethYl) rM' -f2-(4-methvlthiazolyl) 1 thiourea
AP/P/ 9 5 / 0 0 7 2 3
AP Ο Ο Ο 3 β 8
- 27 A solution of 2-phenethyl isothiocyanate (1.63 g, 10 mraol, 1.5 mL), 2-amino-4-methylthiazole hydrochloride (1.51 g, 10 mmol) and Ν,Ν-diisopropylethylamine (1.29 g, 10 mmol, 1.74 mL) in dimethylsulfoxide (10 mL) was heated to
100°C. After 21 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid, saturated sodium bicarbonate solution, water (3x), and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (1% ethyl acetate in dichloromethane), followed by recrystallization from ethyl acetate to provide 1.05 g (38%) of the title product as a very light green crystalline solid:
mp 190-192°C;
IR (KBr, cm'1) 3456, 3169, 3084, 3024, 1565, 1533, 1506, 1214;
XH NMR (300 MHZ, CDCI3) δ 10.92 (s, IH), 10.08 (s, IH) ,
7.33-7.20 (m, 5H), 6.31 (s, IH), 4.04-3.98 (m, 2H), 3.01 (t, J=6.9 Hz, 2H), 2.17 (s, 3H);
MS (El)' m/e 277 (M+) ;
UV (EtOH) 293nra (€=18119), 258nm (€=10137), 204nm (€=18979). Anal. Calcd. for C13H15N3S2:
Theory: C, 56.29; H, 5.45; N, 15.15.
Found: C, 56.53; H, 5.53; N, 15.18.
AP/P/ 9 5 / 0 0 7 2 3
origin^- S
AP Ο Ο Ο 3 8 8
- 28 Example 13
Ν- (2-Phenethyl)-Ν1-12-(4- (ethvlglvoxvlate) thiazolyl) 1 thiourea
A solution of 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) and ethyl 2-amino-4-thiazoleglyoxylate (4.0 g, 20 mmol) in dimethylsulfoxide (20 mL) was heated to o
110 C. After 68 h, the reaction was cooled to room 10 temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid, water (5x), and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (10% ethyl acetate in dichloromethane) and treated with decolorizing carbon to provide 2.37 g (33%) of the title product as a light yellow solid. A sample was recrystallized from ethyl acetate: mp 168-169°C;
IR (KBr, cm'1) 3174, 3029, 1724, 1685, 1558, 1530, 1215,
AP/P/ 9 5 / 0 0 7 2 3
AP Ο Ο Ο 3 8 8
- 29 χΗ NMR (300 MHZ, CDCI3) δ 10.67 (s, 1Η) , 8.21 (S, 1Η) ,
7.34-7.17 (m, 5Η), 4.39 (q, J=7.1 Hz, 2Η), 3.96-3.85 (m,
2Η), 3.09-2.93 (m, 2Η) , 1.40 (t, J=7.1 Hz, 3H);
MS (FD) m/e 363 (M+);
UV (EtOH, 284nm (€=18549), 255nm (€=17141), 204nm (€=23447). Anal. Calcd for C16H17N3O3S2:
Theory: C, 52.87; H, 4.71; N, 11.56.
Found: C, 53.08; H, 4.80; N, 11.55.
Example 14
N- (2-Phenethyl) -N' -(2- (5.6-dimethvlbenzothiazolvl) 1
A solution of 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) and 2-amino-5,6-dimethylbenzothiazole (3.57 g, 20 mmol, in N,//-dimethyl-formamide (50 mL) was heated to 100°C. After 24 h, the reaction was cooled to room temperature and poured into ethyl acetate, with formation of a precipitate. The organic phase was washed with IN hydrochloric acid, saturated sodium bicarbonate solution, water (2x) and brine. The organic layer was filtered and the solid obtained (3.0 g) triturated with 20% ethanol in ethyl acetate to provide 2.91 g (43%) of the title product as a pale yellow solid:
mp 226-'228eC;
AP/P/ 9 5 / 0 0 7 2 3
ΑΡ ο Ο Ο 3 e 8 ., · R
- 30 10
IR (KBr, cm’1! 3178, 3047, 1557, 1530, 1462, 1254, 1220; iH NMR (300 MHZ, DMSO-dg) δ 11.69 (s, IH), 10.30 (s, IH),
7.55 (s, IH), 7.35-7.16 (m, 6H), 3.80-3.73 (m, 2H), 2.90 (t, J=7.0 Hz, 2H), 2.25 (s, 3H) , 2.23 (s, 3H);
MS (El) m/e 341 (M+);
UV (EtOH) 307nm, 253nm, 204nm.
Anal. Calcd for Ci8H19N3S2:
Theory: C, 63.31; H, 5.61; N, 12.31.
Found: C, 63.15; H, 5.63; N, 12.14.
Examal.fi 15
N- (2.-Phenethvll-Ν’ -12 - .(6-methoxybenzothiazolvl) 1 thiourea
AP/P/ 9 5 / 0 0 7 2 3
A solution of 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) and 2-amino-6-methoxybenzothiazole (3.60 g, 20 mmol) in Ν,Ν-dimethylformamide (50 mL) was heated to 100°C. After 16 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid, saturated sodium bicarbonate solution, water (3x) and brine. The organic layer was filtered to provide 550 mg of the title product. The filtrate was concentrated and the
BAD ORIGINAL $
APO 0 0 3 88
V -P resulting solid recrystallized from ethyl acetate to provide, another 830 mg of the title product. Total yield:
1.38 g (20%) of the title product as a fluffy white solid: mp 217-218°C;
IR (KBr, cm’1) 3182, 3050, 1556, 1534, 1473, 1437, 1221,
1055;
1h NMR (300 MHZ, CDCI3) 5 10.99 (s, 1H) , 9.29 (s, 1H) ,
7.46-6.99 (m, 8H), 4.12-4.06 (m, 2H), 3.86 (s, 3H), 3.08 (t, J=6.8 Hz, 2H);
MS (FD) m/e 343 (M+);
UV (EtOH) 312nm (£=22725), 251nm (£=11152), 204nm (£=26183) Anal. Calcd for C17H17N3OS2:
Theory: C, 59.45; H, 4.99; N, 12.23.
Found: C, 59.21; H, 4.97; N, 12.19.
Example 16
2-Amino-4-cvanothia2ole
AP/P/ 9 5 / 0 0 7 2 3
Ethyl 1,2-dihydro-2-ethoxy-1quinolinecarboxylate (6.68 g, 27.0 mmol) was added to a solution of ethyl [2-(tritylamino)thiazol-4-yl]-(Z)hydroxyiminoacetate (11.46 g, 26.7 mmol) in Ν,Ν-dimethylformamide (100 mL) and stirred for 6 h at room temperature.
The reaction was poured into ethyl acetate, washed with IN hydrochloric acid (2x), water (3x) and brine, dried over sodium sulfate, filtered and concentrated. The resulting white foam (9.9 g) was dissolved in dichloromethane (300
original $
AP Ο Ο Ο 3 8 8
357μ
-32mL), treated with triethylsilane (12.44 g, 107 mmol, 17 mL) and trifluoroacetic acid (25 mL) and stirred for 2.5 h at room temperature. The reaction was concentrated in vacuo, dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (1:1 ethyl acetate and hexanes) to provide 2.75 g (82%) of the title product as a white solid:
mp 154-156’C;
IR (KBr, cm-1) 3416, 3291, 3118, 2234, 1638, 1547, 1315, 1108;
1H NMR (300 MHZ, CDCI3) δ 7.23 (s, IH), 5.19 (br s, 2H);
MS (FD) m/e 125 (M+);
UV (EtOH) 278nra (e=4359), 235nm (e=4047), 210nm (e=16728). Anal. Calcd for C4H3N3S:
Theory: C, 38.39; H, 2.42; N, 33.57.
Found: C, 38.65; H, 2.46; N, 33.24.
Example 17
N- (3-PhenvlproPvl)-Ν' -(2-thiazolvl) thiourea
AP/P/ 9 5 / 0 0 7 2 3
BAD ORIGINAL $
APO 00 3 88
-33A solution of 3-phenylpropyl isothiocyanate (500 mg, 2.82 mmol) and 2-aminothiazole (300 mg, 3.0 mmol) in N, N-dimethyl formamide (10 mL) was heated to 100°C. After 20 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid, water (3x), and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (1% ethyl acetate in dichloromethane) and then recrystallized from ethyl acetate to provide 129 mg of the title product. A second crop was recrystallized from 1:1 ethyl acetate/hexanes to provide another 110 mg of the title product. Total yield of the title product: 239 mg (30%, as an off-white solid. A sample was recrystallized again from ethyl acetate: mp 126.5-127.5eC;
IR (KBr, cm1) 3166, 3022, 1574, 1523, 1502, 1215, 1166;
*H NMR (300 MHZ, CDCI3) δ 10.88 (s, IH), 10.42 (S, IH) , 7.37-7.15 (m, 6H) , 6.82 (d, J=3.6 Hz, IH) , 3.82-3.71 (m,
2H,, 2.74 (t, J=7.7 Hz, 2H), 2.12-2.01 (m, 2H,;
MS (FD) m/e 277 (M+);
UV (EtOH) 288nm (e=19598), 256nm (e=11329), 206nm (e=19259).
Anal. Calcd for C13H15N3S2:
Theory: C, 56.29; H, 5.45; N, 15.15.
Found: C, 56.29; H, 5.38; N, 15.00.
AP/P/ 9 5 / 0 0 7 2 3
APO 0 0 3 88
-34Example 18
N-(2-Phenethvl)-Ν'-12- (6-ethoxvbenzothiazolvl)1 thiourea
g, 20 mmol, 3.0 mL) and 2-amino-6-ethoxy-benzothiazole (3.88 g, 20 mmol) in N, N-diraethylformamide (50 mL) was heated to 100eC. After 20 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid, saturated sodium bicarbonate solution, water (3x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was recrystallized from ethyl acetate to provide 649 mg (9%) of the title product as a tan solid: mp 204-205°C;
IR (KBr, cm-1) 3166, 3022, 1574, 1523, 1502, 1435, 1215;
!h NMR (300 MHZ, CDCI3) δ 11.01 (s, IH), 9.77 (s, IH), 7.43-6.95 (m, 8H), 4.08-4.01 (m, 4H), 3.06 (t, J=6.6 Hz,
2H), 1.43 (t, J=6.8 Hz, 3H) ;
MS (FD) m/e 357 (M+>;
AP/P/ 9 5 / 0 0 7 2 3
BAD ORIGINAL $
APO GO 388
- 35 UV (EtOH) 312nm (e=23035), 251nm (e=11355), 204nm (e=26891).
Anal. Calcd for C18H19N3OS2 ··
Theory: C, 60.48; H, 5.36; N, 11.75.
Found: C, 60.21; H, 5.10; N, 11.52.
Example lg tL--(2-Phenethyl) -N’-f2- (4-tert-butvlthiazolvl)1 thiourea
g, 20 mmol, 3.0 mL) and 2-amino-4-tert-butylthiazole (3.13 g, 20 mmol) in Ν, N- di me thy If ormamide (50 mL) was heated to 100°C. After 64 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid, saturated sodium bicarbonate solution, water (2x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was recrystallized from
2C ethyl acetate to provide 2.98 g (47%) of the title product as an off-white crystalline solid:
AP/P/ 9 5 / 0 0 7 2 3
APO00388
- 36 IR (KBr, cm-1) 3173, 2960, 1576, 1514, 1465, 1348, 1204, 1098;
*H NMR (300 MHZ, CDCl3) δ 11.14 (S, IH) , 10.26 (s, IH),
7.31-7.18 (m. 5H) , 6.33 (s, IH), 4.05-3.99 (m, 2H), 3.04 (t, J=7.1 Hz, 2H), 1.14 (s, 9H);
MS (FD) m/e 319 (M+);
UV (EtOH) 292nm (e=20804), 257nm (e=10502), 203nm (e=19085).
Anal. Calcd for C16H21N3S2:
Theory; C, 60.15; H, 6.63; N, 13.15.
Found: C, 59.95; H, 6.66; N, 13.15.
Example 20
N- (2-PhenethyJJ -N-' -(2-14-trifluoromethylthiazolvlll 15 thiourea
AP/P/ 95/00723
A solution of 2-phenethyl isothiocyanate (3.26 20 g, 2C mmol, 3.0 mL) and 2-amino-4-trifluoromethylthiazole (3.84 g, 22.8 mmol, in N,N- dime thyl-formamide (50 mL) was heated to 100°C. After 20 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid, water (3x) and
BAD ORIGINAL
APO00388 brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was recrystallized from 1:1 ethyl acetate/hexanes to provide 846 mg (13%) of the title product as a white solid:
mp 162-163’C;
IR (KBr, cm1) 3166, 3033, 1562, 1516, 1469, 1242, 1126; Th NMR (300 MHZ, CDCI3) 6 10.49 <s, IH), 10.31 (s, IH) ,
7.33-7.19 (m, 6H), 4.01-3.95 (m, 2H), 3.02 (t, J=6.9 Hz, 2H) ;
MS (FD) m/e 331 (M+);
UV (EtOH) 286nm (e=14352), 258nm (e=14149), 205nm (e=24571).
Anal. Calcd for C13H12F3N3S2:
Theory: C, 47.12; H, 3.65; N, 12.68.
Found: C, 47.34; H, 3.85; N, 12.72.
AP/P/ 9 5 / 0 0 7 2 3
A solution of 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) and 2-amino-5-chlorothiazole (2.69 g,
AP000388
- 38 20 mmol) in N,N-dimethylformamide (50 mL) was heated to 100 C. After 20 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid and brine (3x).
The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (1% ethyl acetate in dichloromethane) and then recrystallized twice from ethyl acetate to provide 606 mg (14%) of the title product as an off-white crystalline solid: mp 104.5-105.5°C;
IR (KBr, cm'1) 3284, 1536, 1452, 1347, 901;
!h NMR (300 MHZ, CDCI3) 6 7.33-7.19 (m, 5H), 5.37 (br s,
IH), 3.93-3.87 (m, 2H), 3.16 (s, 6H), 2.93 (t, J=6.8 Hz,
2H);
MS (FD) m/e 208 (M+);
UV (EtOH) 242nm (£=12899), 210nm (£=21286).
Anal. Calcd for C11H16N2S:
Theory: C, 63.42; H, 7.74; N, 13.45.
Found: C, 63.39; H, 7.80; N, 13.67.
AP/P/ 9 5 / 0 0 7 2 3
AP000388
- 3y Example 22
N-(2-Phenvethvl)-Ν’-f2-(4-cvanothiazolvl) thiourea
A solution of 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) and 2-amino-4-cyanothiazole (2.50 g, 20 mmol) in N,N-dimethylformamide (50 mL) was heated to 100°C. After 20 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution, water (3x), and brine. The organic layer was dried over sodLium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (1% ethyl acetate in dichioromethane) and then recrystallized from 1:1 ethyl acetate/hexanes to provide 132 mg of the title product (2%) as a white solid:
mp 169 -17 O’C ;
IR (KBr, cm-1) 3166, 3022, 1574, 1523, 1502, 1215, 1166;
NMR (300 MHZ, CDCI3) 8 10.88 (s, IH), 10.09 (s, IH),
7.50 (s, IH), 7.39-7.23 (m, 5H), 4.00-3.93 (m, 2H), 3.02 (t, J=6.9 Hz, 2H);
MS (FD) m/e 288 (M+);
UV (EtOH) 288nm (£=11104), 258nm (£=17433), 208nm (£=31355).
AP/P/ 9 5 / 0 0 7 2 3
APO 0 0 3 8 8
- 40 Anal. Calcd for C13H12N4S2:
Theory: C, 54.14; H, 4.19; N, 19.43. Found: C, 54.04; H, 4.23; N, 19.73.
Example 22
N-(2-Phenethvl)-N‘-2-(4-(4-ovridvl)-thiaznlvl) thiourea
2-Amino-4-(4-pyridyl)thiazole hydrobromide1 ·2 was slurried with methylene chloride and shaken with saturated sodium bicarbonate solution. The layers were separated and the aqueous washed with methylene chloride and ethyl acetate. The combined organic layers were concentrated. To the solid (1.0 g, 5.6 mmol) was added 215 phenethyl isothiocyanate (0.91 g, 5.6 mmol, O.83mL) in Ν,Νdimethyl formamide (12.5 mL). The resulting suspension was heated to 100°C. After 20.5 h, the reaction was cooled to room tanroerature and poured into ethyl acetate. The organic phase was washed with water (4x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The resulting solid was recrystallized from
AP/P/ 9 5 / 0 0 7 2 3
BAD ORIGINAL $
APO 0 0 3 8 8
- 41 ethyl acetate (3x) to provide 133 mg (7%) of the title product: mp 196.5*C;
IR (KBr, cm'1) 3250, 2939, 1723, 1604, 1506, 1223, 670,
664;
!h NMR (300 MHz, DMSO-dg) δ 11.72 (s, IH), 9.21 (br s, IH),
8.54 (d, J=6 Hz, 2H), 7.82 (s, IH), 7.63 (d, J=6 Hz, 2H), 7.30-7.15 (m, 5H), 3.84-3.77 (m, 2H) , 2.89 (t, J=7 Hz, 2H); MS (FD) m/e 340 (M+) ;
HRMS (FAB) m/e (M+) calcd 341.0895, obs 341.0909;
UV (EtOH) 294nm (8=23935), 231nm (£=16356), 203nm (£=25793).
(1) Nielsen, A.T. and Platt, E.N. Heterocyclic Chem..
1969, vol 6 p 896.
(2) Brown, Cowden, Grigg, Kavulak Aust. J. Chem. 1980, 33,
2291.
AP/P/ 9 5 /\) h 7 2 3 bad original
APO00388
- 42 Example 24
M- 12-Phenethvl) -N‘ -I2z.L4r (4.-hiphenvl) -thiazolvll thiourea
A solution of 2-phenethyl isothiocyanate (0.82 g, 5 mmol, 0.75 mL) and 2-amino-4-(4-biphenyl) thiazole (1.26 g, 5 mmol) in N,N-dimethylformamide (12.5 mL) was heated to 100°C. After 19.5 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic solution was washed with IN hydrochloric acid. The mixture was filtered and the filtrate was separated and the organic phase washed with saturated sodium bicarbonate solution, water (4x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The material was purified by flash chromatography on silica gel (1% ethyl acetate in dichloromethane to 2% ethyl acetate in dichloromethane) to provide 372 mg of the title product (18%). The yellow solid was recrystallized from ethyl acetate:
mp 208.5-209*0;
AWPl 95/00723
BAD ORIGINAL
APO 0 0 3 88
- 43 IR (KBr, cm-1) 3437, 3172, 3029, 1570, 1553, 1511, 1211, 1060, 738;
XH NMR (300 MHz, DMSO-dg) d 11.72 (s, 1H> , 9.54 (br s, IH),
7.86-7.80 (m, 2H), 7.78-7.68 (m, 4H), 7.58 (s, IH), 7,525 7.44 tin, 2H> , 7.41-7.35 (in. IH) , 7.34-7.29 (m, 4H) , 7.277.20 (m, IH), 3.92-3.84 (m, 2H, , 2.98 (t, J=3 Hz, 2H) ;
MS (FD) m/e 415 (M+);
UV (EtOH) 293nm, 212nm.
Anal. Calcd for C24H21N3S2:
Theory: C, 69.36; H, 5.09; N, 10.11.
Found: C, 69.08; H, 5.10; N, 9.99.
Example ,25
N- (2-Phengthvli -_N-‘ -2-f4- (l- (l-ethyoxvcarbonlvl) -(3-t-
AP/P/ 9 5/ 0 0 7 2 3
APO 0 0 3 8 8
- 44 2-Amino-4 - (1- (1-ethoxycarbonyl) -(3-t-butoxycarbonyImethoxy) imino)thiazole (2.64 g, 8 mmol) and 2phenethyl isothiocyanate (1.31 g, 8 mmol, 1.2 mL) in N,lidimethylformamide (20 mL) were heated to 100°C. After 24 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid, saturated sodium bicarbonate solution, water (3x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The resulting solid was triturated with ethyl acetate to provide 801 mg (20%) of the title product:
mp 188.5’C;
IR (KBr, crrT1) 3293, 2975, 1749, 1594, 1543, 1453, 1382, 1231, 1154, 1054, 748, 698;
*H NMR (300 MHz, DMSO-dg) d 11.85 (s, IH) , 8.46 (br S,1H), 7.29-7.17 (m, 5H), 4.59 (s, 2H), 4.31-4.24 (q, J=7.1 Hz,
2H), 3.70-3.64 (m, 2H), 2.82 (t, J=7.1 Hz, 2H), 1.36 (s,
9H) , 1.23 (t, J= 7.1 Hz, 3H);
MS (FD) m/e 492 (M+) ;
UV (EtOH) 292nm, 257nm (£=16356), 203nm.
Anal. Calcd for C22H28N4OsS2:
Theory: C, 53.64; H, 5.73; N, 11.37.
Found: C, 53.67; H, 5.83; N, 11.34.
Example 26
N- (2-Phenethvl).-N·'-2-f 4-t-.butvIr5.-methvlthiazolvn thiourea
K>
CM
L 0 0 / Q 6 /d/dV
BAD ORIGINAL
APO00388
- 45 2-Amino-4-t-butyl-5-methylthiazole (1.87 g, 11 mmol) and 2-phenethyl isothiocyanate (1.80 g, 11 mmol, 1.64 mL) in Ν,Ν-dimethylformamide (25 mL) were heated to 100°C.
After 18.5 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid, saturated sodium bicarbonate solution, water (3x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The resulting solid was triturated with ether to provide 1.02 g (28%) of the title product: mp 153-153.5’C;
IR (KBr, cm’1) 3171, 2966, 1474, 1534, 1510, 1455, 1346, 1221, 1186, 755, 704;
XH NMR (300 MHz, DMSO-dg) δ 11.28 (BR S, IH), 9.90 (BR S,
IH), 7.28-7.14 (Μ, 5H) , 3.78-3.34 (Μ, 2H), 2.84 (T, J=7 Hz, 2H), 2.27 (s, 3H), 1.16 <s, 9H);
MS (FD) m/e 333 (M+);
UV (EtOH) 297nm (£=19835), 257nm (£=9954), 202nm (£=21059).
Anal. Calcd for C17H23N3S2:
Theory: C, 61.22; H, 6.95; N, 12.60.
Found: C, 61.42; H, 6.92; N, 12.55.
Example 27
R-.i27E.heP£lhyll--JL.,z.I.5--inethvl--f2-(1,3,4-thiadiazolvl) 11 thiourea
A solution of 2-amino-5-methyl 1,3,4-thiadiazole (2.30 g, 20 mmol) and 2-phenethyl isothiocyanate (3.26 g, mmol', 3.0 mL) in N,N-dimethylformamide (50 mL) was £ 2 L u U / 5 o /d/dV heated to 100°C for 18 h. The reaction was cooled to room temperature and the solvent was removed in vacuo. The
APO00388
- 46 resultant solid was crystallized from ethyl acetate to provide 1.86 g (33%) of the title product as a white solid: IR (KBr, err.-1) 3323, 3031, 1640, 1540, 1444, 1385, 781,
697, 652;
!h NMR (300 MHz, DMSO-d6) δ 12.4 (br s, IH) , 8.75 (br s,
IH), 7.4-7.2 (m, 5H), 3.85-3.75 (m, 2H) , 2.9 (t, J=7 Hz,
2H), 2.54 (s, 3H);
MS (FD) m/e 278 (M+);
UV (EtOH) 280nm (6=10188), 253nm (6=11849), 205nm (6=19724).
Example 28
Ph-enethvl) -Ν'-12-pvrlmidinvl) thiourea
A solution of 2-aminopyrimidine (1.90 g, 20 mmol) and 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) in Ν,Ν-dimethylformamide (50 mL) was heated to 120°C for 40 h. The reaction was cooled to room temperature and the solvent was removed in vacuo. The resultant solid was recrystallized twice from ethyl acetate to provide 0.90 g (17%) of the title product as white needles:
IR (KBr, cm-1) 3325, 1588, 1524, 1434, 1415, 1333, 1228, 1154, 797;
XH NMR (300 MHz, DMSO-c?6) 5 11.25 (br s, IH) , 10.65 (br s,
IH), 8.6 (d, J=5 HZ, 2H) 7.4-7.2 (m, 6H), 3.85-3.75 (m,
2H) , 2.9 (t, J=7 Hz, 2H) ;
MS (FD) m/e 258 (M+);
UV (EtOH) 286nm (6=17644), 267nm (6=15834), 244nm (6=12312), 205nm (6=21839).
Anal. Calcd for C13H14N4S:
Theory: C, 60.44; H, 5.46; N, 21.69.
Found: C, 60.15; H, 5.48; N, 21.89.
AP/P/ 9 5 / 0 0 7 2 3
BAD ORIGINAL Ά
APO Ο Ο 3 8 8
- 47 Example 23.
Ν-!2-Phenethyl)-Ν’-f2-(4-(4-chlorophenvl)thiazolyl)Ί £hi£UE£a
A solution of 2-phenethyl isothiocyanate (0.77 5 g, 4.75 mmol) and 2-amino-4-(4-chlorophenyl)thiazole (1.0 g, 4.75 mmol) in N,N-dimethylformamide (10 mL) was heated to 120°C 20 h. The solvent was removed in vacuo. The resultant solid was recrystallized from ethyl acetate to provide 0.30 g (17%) of the title product as a yellow solid:
IR (KBr, cm’1) 3176, 3029, 1579, 1515, 1231, 737, 698;
3H NMR (300 MHz, DMSO-άζ) δ 11.70 (br s, IH), 9.40 (br s, IH), 7.74-7.54 (m, 5H), 7.36-7.18 (m, 5H), 3.9-3.8 (m, 2H),
2.96 (t, J=6 Hz, 2H);
MS (FD) m/e 373 (M+);
UV (EtOH) 273nm (£=35089), 247nm (£=21894), 202nm (£=22213). Anal. Calcd for C18H3.6N3S2CI:
Theory: C, 57.82; H, 4.31; N, 11.24.
Found: C, 57.55; H, 4.24; N, 11.26.
Example.. 3 Q
Ν-ί2-phenethyl)-Ν' -(2-(6-chloro)benzothiazolyl) thiourea
A solution of 2-phenethyl isothiocyanate (3.26 g, 20 mmol) and 2-amino-6-chlorobenzothiazole (3.69 g, 20 mmol) in N,N-dimethylformamide (50 mL, was heated to 120°C for 24 h. The solvent was removed in vacuo. The resultant solid was recrystallized from ethyl acetate to provide 3.68 g (53%, of the title product as a white solid:
IR (KBr, cm1) 3165, 3021, 1574, 1522, 1501, 1289, 1215;
lH NMR (300 MHz, CDCI3) δ 12.0 (br s, IH), 9.8 (br s, IH),
8.1-7.2 (m, 8H), 3.85 (m, 2H), 2.95 (t, J=7 Hz, 2H);
AP/P/ 95/00723
BAD qBIGINAL
APO00388
- 4S MS (FD) m/e 347 (M+);
UV (EtOH) 304nm, 292nm, 248nm, 220nm, 205nm.
Example 31
N-i2-fhen.eLhyJJ.-N’- f5-ethvl-Γ2- (1.3.4-thiadiazolyl)) 1
Lhuionrsa
A solution of 2-amino-5-ethyl-l,3,4-thiadiazole (2.58 g, 20 mmol) and 2-phenethyl isothiocyanate (3.26 g, mmol, 3.0 mL) in N, N-dimethylformamide (50 mL) was heated to 120°C for 8 h. The reaction was cooled to room temperature and the solvent was removed in vacuo. The resultant solid was crystallized from ethyl acetate to provide 2.45 g (33%) of the title product as a white solid: IR (KBr, cm1) 3317, 1645, 1536, 1448, 1384, 783, 693, 651;
1H NMR (300 MHz, DMSO-c?6) δ 12.4 (br s, IH) , 8.75 (br s,
IH), 7.4-7.2 (m, 5H), 3.85-3.75 (m, 2H), 3.0-2.8 (m, 4H), 1.25 (t, J=7 Hz, 3H);
MS (FD) m/e 292 (M+);
UV (EtOH) 281nm (£=13028), 253nm (£=13615), 206nm (£=23674).
Example 32
Nmi2mPhfinethyl).-N' - flmchlorophenyll thiourea
A solution of 4-chloroaniline (2.55 g, 20 mmol) and 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) in
N,W-dimethylformamide (50 mL) was heated to 120°C for 18 h.
The reaction was cooled to room temperature and the solvent was removed in vacuo. The resultant solid was crystallized from ethyl acetate to provide 1.50 g (26%) of the title £ I L 0 0 / S 6 /d/dV
AP000388
- 49 IR (KBr, αη-1) 3166, 3021, 1523, 1501, 1289, 1079, 802,
737, 695;
^H NMP. (3 00 MHz, DMSO-d6) 6 9.6 (br s, IH), 7.9 (br s, IH),
7.5-7.2- (m. 9H), 3.8-3.65 (m, 2H), 3.0-2.8 (t, J=7 Hz, 2H) ;
MS (FD) m/e 290 (M+) ;
UV (EtOH) 270nm (£=14107), 247nm (£=18128), 206nro (£=27795). Anal. Calcd for C15H15N2SCI:
Theory: C, 61.95; H, 5.20; N, 9.63.
Found: C, 62.19; H, 5.46; N, 9.87.
Example
N- (2-Phenethvl)-Ν' -f3-chlorophenvl] thiourea
A solution of 3-chloroaniline (2.55 g, 20 nmol) and 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) in
N, N-dimethyl formamide (50 mL) was heated to 120°C for 20 h.
The reaction was cooled to room temperature and the solvent was removed in vacuo. The resultant yellow oil was purified by HPLC on silica gel to provide 0.95 g (16%) of the title product as a white solid:
IR (KBr, cm-1, 3310, 1591, 1542, 1495;
!h NMR (300 MHz, DMSO-dg) δ 9.85 (br s, IH,, 7.9 (br s,
IH), 7.65-7.2 (m, 9H), 3.8-3.65 (m, 2H), 3.0-2.8 (t, J=7 Hz, 2H);
MS (FD) m/e 290 (M+);
UV (EtOH) 250nm (£=17296), 209nm (£=29630).
Anal. Calcd for C15H15N2SCI:
Theory: C, 61.95; H, 5.20; N, 9.63.
Found: C, 61.65; H, 5.44; N, 9.84.
AP/P/ 9 5 / 0 0 7 2 3 bad original
AP ο ο Ο 3 8 8
- 50 Example 34
Ν-in-PropyU-Ν'cJ2-thiazovll thiourea
A solution of 2-aminothiazole (2.0 g, 20 mmol) and n-propyl isothiocyanate (2.0 g, 20 mmol) in Ν,Νdimethylformamide (50 mL) was heated to 120°C for 20 h.
The reaction was cooled to room temperature and the solvent was removed in vacuo. The resultant yellow oil was recrystallized twice from ethyl acetate to provide 0.42 g (10%) of the title product as a white solid:
IR (KBr, cm’1) 3179, 1556, 1514, 1471, 680;
*H NMR (300 MHz, DMSO-c?6) δ 11.55 (br s, 1H) , 9.7 (br s,
1H), 7.4 (d, J=5 Hz, 1H), 7.1 (d, J=5 Hz, 1H), 3.5 (m, 2H), 1.6 (m, 2H), 0.95 (t, J=7 Hz, 3H);
MS (FD) m/e 201 (M+);
UV (EtCH) 288nm (£=19469), 256nm (£=10151), 202nm (£=11550). Anal. Calcd for C7H11N3S2:
Theory: C, 41.77; H, 5.51; N, 20.87.
Found: C, 42.02; H, 5.61; N, 20.93.
Example 35
N- (2-phenethyl) I2--JA, 5^6.7-tetrahvdrobenzothiazolvl) 1 thiourea
A solution of 2-phenethyl isothiocyanate (1.63 g, 10 mmol) and 2-amino-4,5,6,7-tetrahydrobenzothiazole (1.54 g, 10 mmol) in N,N-dimethylformamide (25 mL) was heated to 120°C for 48 h. The solvent was removed in vacuo. The resultant solid was recrystallized from ethyl acetate to provide 0.32 g (11%) of the title product as a white solid:
IR (KBr, cm-1) 3165, 3021, 2923, 1601, 1529, 1501, 1261,
1225; __-_
AP/P/ 9 5 / 0 0 7 2 3 bad original
APOΟΛ388
- 51 2H NMR (300 MHz, DMSO-dg) δ 11.5 (br s, IH), 10.0 (br s,
IH), 7.4-7.2 (m, 5H), 3.85 (m, 2H), 2.95 (t, J=7 Hz, 2H),
2.6-2.4 (m, 4H), 1.75 (m, 4H);
MS (FD) m/e 317 (M+);
UV (EtOH) 299nm (£=11440), 258nm (£=6011), 207nm (£=10579).
Example 36
N-(2-phenethvl)-N‘-f2-benzothiazolvl1 thiourea
A solution of 2-phenethyl isothiocyanate (3.26 10 g, 20 mmol, 3.0 mL) and 2-aminobenzothiazole (3.0 g, 20 mmol) in toluene (50 mL) was heated to reflux. After 5 h, the reaction was cooled to room temperature and poured into tO ethyl acetate, washed with water, IN aqueous HCl, water, OJ saturated sodium bicarbonate, and brine. The organic layer 15 was concentrated and the residue recrystallized from ethyl acetate to provide 1.8 g (29%) of the title product: mp 203-207°C;
IR (KBr, cm-1) 3181, 3045, 1697, 1557, 1523, 1451, 1440,
1244, 749;
20 1-H NMR (300 MHz, CDCl3/DMSO-d6) δ 11.7 (br s, IH,, 10.6
s, IH), 7.8-7.2 (m, 9H), 3.95 (m, 2H), 3.05 (t, J=7 Hz,
2H) ;
MS (FD) m/e 313 (M+);
UV (EtOH) 300nm (£=24241), 207 nm (£=28964).
25 Anal. Calcd for C16H15N3S2:
Theory : C, 61.31; H, 4.82; N, 13.41.
Found: C, 61.03; H, 4.67; N, 13.19.
AP/P/ 9 5 / 0 0 7
ORIGINAL
APO 0 0 3 88
- 52 Example 37
N=i2-ch£L£Lhvl) -Ν' - f2- (4-methvl)benzothiazolyl 1 thiourea
A solution of 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) and 2-amino-4-methylbenzothiazole (3.3 g, 20 mmol; in toluene (50 mL) was heated to reflux. After 5 h, the reaction was cooled to room temperature and poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acetate to provide 1.68 g (26%) of the title product:
mp 185-188*-C;
IR (KBr, cm1) 3170, 3024, 1571, 1525, 1219, 767, 742, 698; !h NMR (300 MHz, CDCl3/DMSO-dg) 6 11.4 (br s, IH) , 10.9 (br s, IH), 7.6-7.1 (m, 8H), 4.05 (m, 2H), 3.05 (t, J=7 Hz,
2H), 2.37 (s, 3H);
MS (FD) m/e 327 (M+);
UV (EtOH) 303nm (£=27416), 204 nm (£=30294).
Anal. Calcd for C17H17N3S2:
Theory: C, 62.35; H, 5.23; N, 12.83.
Found: C, 62.56; H, 5.37; N, 12.77.
Example 38
N- (2-phenethvl)-Ν'-f2-(4-methoxv)benzothiazolyl) thiourea
A solution of 2-phenethyl isothiocyanate (3.26 25 g, 20 mmol, 3.0 mL) and 2-amino-4-methoxybenzothiazole (3.2 g, 20 mmol) in N, N-dimethyl formamide (20 mL, was heated at 115°C for 24 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water,
IN aqueous HCl, water, saturated sodium bicarbonate, and
AP/P/ 9 5 / 0 0 7 2 3
APO00388
- 53 recrystallized from ethyl acetate to provide 0.97 g (14%) of the title product: mp 205-207°C;
IR (KBr, cm1) 3165, 3021, 1574, 1522, 1215, 736, 695, 655; 5 1H NMR (300 MHz, DMSO-d6) δ 12.4 (br s, IH), 9.9 (br s,
IH), 7.6-7.0 (m, 8H), 3.9 (s, 3H) , 3.85 (m, 2H), 2.95 (t, J=7 Hz, 2H) ;
MS (FD) m/e 343 (M+);
UV (EtOH) 293nm (6=20046), 248 nm (6=15731), 210 nm (6=38172).
Example,, 19.
N- (2-phenethvl)-Ν'-f2-(4-chloro)benzothiazolvn thiourea
A solution of 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) and 2-amino-4-chlorobenzothiazole (3.7 g, 20 mmol) in Ν,Ν-dimethylformamide (20 mL) was heated at 115°C for 24 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water,
IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acetate to provide 2.56 g (37%) of the title product:
mp 216-217°C;
IR (KBr, cm1) 3166, 2940, 1568, 1527, 766, 733, 673;
ΧΗ NMR (300 MHz, DMSO-dg) δ 12.2 (br s, IH), 9.3 (br s,
IH) , 7.6-7.0 (m, 8H), 3.85 (m, 2H), 2.95 (t, J=7 Hz, 2H);
MS (FD) m/e 347 (M+);
UV (EtOH) 301nm (6=20231), 249 nm (6=17615), 211 nm (6=31440) .
AP/P/ 9 5 / 0 0 7 2 3
AP ο 0 0 3 8 8
- 54 Example 40
N.-12-Phenethyl)-N'-(3-11,2,4-triazolvl) 1 thiourea
A solution of 3-amino-l,2,4-triazole (1.70 g, 20 mmol) and 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) in N,N-dimethylformamide (20 mL) was heated to 115°C for 24 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acetate to provide 0.99 g (20%) of the title product: mp 160-162’C;
IR (KBr·, cm1) 3160, 3061, 2872, 1581, 1535, 1467, 1167, 977, 743, 681;
iH NMR (300 MHz, DMSO-dg) 6 13.9 (br s, IH), 10.85 (br s, IH) , 10.0 (br s, IH), 7.4-7.2 (m, 6H), 3.85 (m, 2H), 2.95 (t, J=7 Hz, 2H);
MS (FD) m/e 247 (M+);
UV (EtOH) 261nm (£=21785), 229 nm (£=11918), 206 nm (£=17437) .
Anal. Calcd for C11H13N5S:
Theory: C, 53.42 H, 5.30; N, 28.32.
Found: C, 53.69; H, 5.50; N, 28.07.
Example 41
N- (2.-PhenethyllrN’_-J3-mLinQlinvl1 thiourea
A solution of 3-aminoquinoline (2.90 g, 20 mmol) and 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) in N, .N-dimethylformamide (20 mL) was heated to 90°C for 72 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water,
AP/P/ 95/00723
APO 0 0 388
- 55 saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acetate to provide 3.62 g (59%) of the title product: mp 162-164°C;
IR (KBr, cm-1, 3143, 1537, 1493, 1350, 1283, 1239, 749,
705;
NMR (300 MHz, DMSO-d6> δ 9.9 (br s, IH) , 8.87 (d, J=4 Hz), IH), 8.35 (br s, IH,, 8.0 (d, J=8 Hz, IH), 7.9 (d, J=8 Hz, IH), 7.7-7.2 (m, 8H) , 3.8 (m, 2H,, 2.95 (t, J=7 Hz,
2H);
MS (FD, m/e 308 (M+);
UV (EtOH) 331nm (€=5945), 257nm (€=27215), 247nm (€=28319), 212 nm (€=37613).
Example 42
M- (2z?h^ethy.Il ~N‘ - (2- (4-aethvl)r>vrimidinel thiourea
A solution of 2-aminopyrimidine (1.90 g, 20 mmol) and 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) in N, N-dimethylformamide (20 mL, was heated to 115°C for 24 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acetate to provide 1.21 g (22%, of the title product: mp 174-17 6°C;
IR (KBr, cm’1) 3184, 3034, 1561, 1409, 1344, 1291, 1165,
1030, 836, 792;
!h NMR (300 MHz, DMSO-dg) δ 11.3 (br s, IH), 10.45 (br s,
IH), 8.4 (d, J=5 Hz, 2H) 7.4-7.2 (m, 5H), 7.0 (d, J=5 Hz,
1H), 3.95-3.75 (m, 2H,, 2.9 (t, J=7 Hz, 2H), 2.3 (s, 3H) ;
£ 2 L 0 0 / ς 6 /d/dV bad original
ΑΡ ο Ο Ο 3 8 8
- 56 MS (FD) m/e 272 (M+);
UV (EtOH) 274nm (£=25263), 248nm (£=15528), 203nra (£=17107). Anal. Calcd for C14H16N4S:
Theory: C, 61.74; H, 5.92; N, 20.57.
Found: C, 61.44; H, 6.11; N, 20.38.
Example 43
N- (2-phenethyl)-N’-r2-(4-(4-fluoroohenvl))thiazolyl) thiourea
A solution of 2-phenethyl isothiocyanate (1.63 g, 10 mmol), triethylamine (1.01 g, 10 mmol), and 2-amino4-(4-fluorophenyl) thiazole hydroiodide (3.2 g, 10 mmol) in Ν,Ν-dimethylformamide (20 mL) was heated to 100°C for 24 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCI, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acetate to provide 1.06 g (30%) of the title product: mp 224-228°C;
IR (KBr, cm-1) 3178, 3030, 1553, 840, 737, 670;
Ih NMR (300 MHz, DMSO-dg) δ 11.70 (br s, IH), 9.50 (br s, IH), 7.8-7.2 (m, 10H), 3.90-3.81 (m, 2H), 2.95 (t, J=6 Hz, 2H) ;
MS (FD) rn/e 357 (M+);
UV (EtOH) 282nm (£=15755), 264nm (£=17277), 239nm (£=13046), 209nm (£=18271).
Anal. Calcd for C18H15N3S2F:
Theory: C, 60.42; H, 4.48; N, 11.74.
AP/P/ 9 5 / 0 0 7 2 3
APO00388
- 57 Example- Al
N-(2-phenethvl)-N‘-f2-(4-thiazolvlacetic acid] thiourea methyl ester
A solution of 2-phenethyl isothiocyanate (0.82 5 g, 5 mmol) and 2-aminothiazoleacetic acid methyl ester (0.85 g, 5 mmol) in N,N-dimethylformamide (20 mL) was heated to 100°C for 72 h, the reaction was cooled to room temperature and poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acetate to provide 0.52 g (31%) of the title product:
mp 125-127°C;
IR (KBr, cm-1) 3168, 3085, 1740, 1557, 1524, ;
Ih NMR (300 MHz, DMSO-dg) δ 11.6 (br s, IH), 9.4 (br s,
IH), 7.4-7.2 (m, 5H), 6.85 (s, IH), 3.8 (m, 2H), 3.65 (s, 2H), 3.6 (s, 3H), 2.9 (t, J=7 Hz, 2H) ;
MS (FD) m/e 335 (M+);
UV (EtOH) 291nm (£=19133), 258nm (£=10917), 202nm (£=21433).
Anal. Calcd for C15H17N3S2O2:
Theory: C, 53.71; H, 5.11; N, 12.53.
Found: C, 53.96; H, 5.16; N, 12.79.
Example 45
N.-.12-phenethyJJ=N'- f 2-th iazoly 1.,1 thiourea
A solution of 2-phenethyl isothiocyanate (7.5 g,
45.9 mmol) and 2-aminothiazole (4.6 g, 45.9 mmol) in N,Ndimethylformamide (100 mL) was heated at 115eC for 12 h.
The reaction was cooled to room temperature, poured into
AP/P/ 9 5 / 0 0 7 2 3
APO 0 0 38 8
- 53 was concentrated and the residue recrystallized twice from ethyl acetate to provide 5.7 g (47%) of the title product: IR (KBr, cm’l) 3187, 3033, 2978, 1569, 1515, 1470, 1454, 1216, 1170, 1063;
XH NMR (300 MHz, DMSO-dg) δ 11.6 (br s, IH), 9.7 (br s,
IH), 7.4-7.2 (m, 6H) , 7.1 (d, J=3 Hz, IH), 3.8 (m, 2H), 2.9 (t, J=7 Hz, 2H);
MS (FD) m/e 263 (M+);
UV (EtOH) 288nm (£=19656), 257 nm (£=11658), 203 nm 10 (£=20054).
Anal. Calcd for C12H13N3S2:
Theory: C, 54.72 H, 4.97; N, 15.95.
Found: C, 54.63; H, 5.02; N, 15.85.
Example 46
N-(2-f1-cvclohexenvllethvl)-N1-f2-thiazolvl1 thiourea
A solution of 2-(1-cyclohexenyl)ethyl isothiocyanate’ (3.3 g, 20 mmol) and 2-aminothiazole (2.0 g, 20 mmol) in Ν,Ν-dimethyl formamide (20 mL) was heated at 100°C for 24 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acetate to provide 2.66 g (50%) of the title product: mp 147-148°C;
IR (KBr, cm1) 3170, 3118, 2989, 1566, 1513, 1180, 706;
Ih NMR (300 MHz, DMSO-dg) δ 11.6 (br s, IH) , 9.7 (br s,
IH), 7.38 (d, J=3 Hz, IH), 7.1 (d, J=3 Hz, IH), 5.45 (br s,
IH), 3.65 (m, 2H), 2.25 (t, J=7 Hz, 2H), 1.9 (m, 4H), 1.5 _(m, 4H) ;_______
AP/P/ 9 5 / 0 0 7 2 3
BAD ORIGINAL
ΑΡ ο Ο Ο 3 8 8
- 59 MS (FD) m/e 267 (Μ*);
UV (EtOH) 288nm (€=19663), 256 run (€=10534), 201 nm (€=14819).
Anal. Calcd for C12H13N3S2:
Theory: C, 53.89 H, 6.41; N, 15.71.
Found: C, 54.15; H, 6.52; N, 15.84.
Example 47
N-(2-phenethvl).-N‘- f 2-(4-thiazolvlacetic acidl thiourea
A solution of 2-phenethyl isothiocyanate (3.62 g, 20 mmol) and 2-aminothiazoleacetic acid ethyl ester (3.72 g, 20 mmol) in N, N-dimethylformamide (20 mL) was heated to 100°C for 24 h, the reaction was cooled to room temperature and poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue was purified by HPLC on silica gel to provide 1.7 g (24%) of the title product:
mp 80-83°C;
IR (KBr, cm’1) 3184, 3109, 1730, 1580, 704, ;
1h NMR (300 MHz, DMSO-dg) δ 11.6 (br s, IH) , 9.4 (br s,
IH), 7.4-7.2 (m, 5H). 6.85 (s, IH), 4.1 (q, J=7 Hz, 2H),
3.8 (m, 2H), 3.65 (S, 2H), 2.9 (t, J=7 Hz, 2H), 1.2 (t, J=7
Hz, 3H);
MS (FD) m/e 349 (M+);
UV (EtOH) 291nm (€=15025), 250nm (€=10893), 203nm (€=24071). Anal. Calcd for C16H19N3S2O2:
Theory: C, 54.99; H, 5.48; N, 12.02.
Found: C, 55.24; H, 5.62; N, 11.96.
AP/P/ 9 5 / 0 0 7 2 3 bad original
APO 0 0 3 8 8
- 60 Example 48
N-(2-Phenethvll.-M’r-f2-i4-thiazplvlacetic acid) thiourea
A solution of N-(2-phenethyl)-N*-(2-(45 thiazolylacetic acid] thiourea ethyl ester (0.7 g, 2.0 mmol) and IN NaOH (2.5 mL, 2.5 mmol) in 50 mL of 1/1 acetonitrile-water was stirred at room temperature for 24 h. The reaction was poured into ethyl acetate and washed with saturated sodium bicarbonate. The aqueous layer was acidified to pH 2 with IN HCl and extracted with ethyl acetate. The organic extracts were washed with brine and concentrated. The residue was crystallized from ethyl acetate to provide 0.29 g (45%) of the title product: mp 188-19 0°C;
IR (KBr, cm-1) 3200-2800 (br), 1659, 1586, 1377, 671, ;
AP/P/ 9 5 / 0 0 7 2 3
1h NMR (300 MHz, DMSO-dg) δ 12.0 (br s, 2H), 9.6 (br s,
IH) , 7.4-7.2 (m, 5H), 6.85 (s, IH), 3.8 (m, 2H,, 3.65 (s,
2H) , 2.9 (t, J=7 Hz, 2H);
MS (FD) m/e 322 (M+ ) ;
UV (EtOH) 291nm (£=19464), 257nm (£=10601), 202nm (£=20396) .
Anal. Calcd for C14H15N3S2O2:
Theory : C, 52.32; H, 4.70; N, 13.07.
Found: C, 52.58; H, 4.88; N, 13.34.
Example.49
N- (benzvl).-Ν’- f2-thiazolvn thiourea
A solution of benzyl isothiocyanate (1.5 g, 10 mmol) and 2-aminothiazole (1.0 g, 10 mmol, in N,N-dimethylformamide (25 mL, was heated at 100°C for 12 h. The
APO00388
- 61 saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized twice from ethyl acetate to provide 1.15 g (46%) of the title product: mp 165-167°C;
IR (KBr, cm'1) 3171, 3038, 1560, 1509, 1451, 1183, 972,
691;
NMR (300 MHz, DMSO-dg) δ 11.7 (br s, IH), 9.9 (br s,
IH) , 7.4-7.2 (m, 6H), 7.05 (d, J=3 Hz, IH), 4.8 (m, 2H, ;
MS (FD) m/e 249 (M+);
UV (EtOH) 289nm (£=19103), 257 nm (£=12196), 204 nm (£=21328) .
Anal. Calcd for C11H11N3S2:
Theory: C, 52.99 H, 4.47; N, 16.85.
Found: C, 53.09; H, 4.50; N, 16.77.
Example 5Q
N-i2-PhenethyH-«dr- (2-pyrazinvl) thiourea A solution of 2-aminopyrazine (1.90 g, 20 mmol) and 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) in 20 N, N-dimethylformamide (50 mL) was heated to 100°C for 17 h.
The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized twice from ethyl acetate to provide 0.95 g (18%) of the title product: mp 142-143°C;
IR (KBr, cm1) 3181, 3049, 1606, 1533, 1472, 1314, 1221,
862, 725;
*H NMR (300 MHz, DMSO-dg) 8 11.02 (br s, IH), 10.95 (br s,
AP/P/ 9 5 / 0 0 7 2 3
APO00388
- 62 IH), 7.4-7.2 (m, 5H), 3.85-3.75 tin, 2H), 2.9 (t, J=7 Hz,
2H) ;
MS (FD) m/e 258 (M+);
UV (EtOH) 318nm (£=10579), 263nm (£=17922), 202nm (£=15887). 5 Anal. Calcd for C13H14N4S:
Theory: C, 60.44; H, 5.46; N, 21.69.
Found: C, 60.45; H, 5.63; N, 22.02.
Example 51
N- (2-?henethvl)-Ν'-Ώ-Pvrazolyl) thiourea
A solution of 3-aminopyrazole (1.66 g, 20 mmol) and 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) in N, N-dimethylformamide (50 mL) was heated to 100°C for 18.5 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCI, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized twice from ethyl acetate to provide 2.38 g (48%) of the title product:
mp 142-144°C;
IR (KBr, cm-1) 3397, 3207, 3078, 1576, 1537, 1255, 1182,
751;
1h NMR (300 MHz, DMSO-dg) δ 12.4 (br s, IH), 10.35 (br s, IH), 9.85 (br s, IH), 7.6 (s, IH), 7.4-7.2 tin, 5H), 5.83 (s, IH), 3.75 (in, 2H) , 2.85 (t, J=7 Hz, 2H) ;
MS (FD) m/e 246 (M+);
UV (EtOH) 264nm (£=21473), 204nm (£=17842).
AP/P/ 9 5 / 0 0 7 2 3
Anal. Calcd for C12H14N4S:
Theory: C, 58.51; H, 5.73; N, 22.74.
APO00388
- 63 Example 52
Preparation of N-(2-Fhenethvl)-Ν'-(phenvl) thiourea
A solution of aniline (1.86 g, 20 mmol) and 2phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) in Ν,Νdimethylformamide (50 mL) was heated to 100°C for 18 h.
The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl ether/hexanes to provide 2.88 g (56%) of the title product: mp 102-104°C;
IR (KBr; cm-1) 3375, 1592, 1542, 1493, 1250, 1000, 695;
!h NMR (300 MHz, CDCI3) δ 7.85 (br s, IH), 7.5-7.0 (m,
10H), 6.0 (br s, IH), 3.9 (m, 2H), 2.9 (t, J=7 Hz, 2H);
MS (FD) m/e 256 (M+);
UV (EtOH) 248nm (6=15081), 206nm (€=25573).
Anal. Calcd for C15H16N2S:
Theory: C, 70.28; H, 6.29; N,
Found: c. 70.14; H, 6.37; N,
AP/P/ 9 5 / 0 0 7 2 3
Example 53
N- (.ethyl) -Ν'- (2?xhiazQlY.ll.thiourea A solution of ethyl isothiocyanate (1.74 g, 20 mmol) and 2-aminothiazole (2.0 g, 20 mmol) in Ν,Ν-dimethylformamide (50 mL) was heated at 100°C for 23 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized twice from ethyl acetate to provide 0.48 g (13%) of the title product:
BAD ORIGINAL ffl
APOOO 388
- 64 mp 135-136°C;
IR (KBr, cm'1) 3165, 3021, 1574, 1501, 1435, 1366, 1215, 1179, 695;
!h NMR (300 MHz, DMSO-dg) 5 10.4 (br s, 2H), 7.4 (d, J=3 5 Hz, IH), 6.8 (d, J=3 Hz, IH), 3.7 (m, 2H), 1.4 (t, J=7 Hz,
3H) ;
MS (FD) m/e 187 (M+);
UV (EtOH) 287nm (6=19544), 256 nm (6=10213), 202 nm (6=11588).
Anal. Calcd for C6H9N3S2:
Theory: C, 38.48 H, 4.84; N, 22.44.
Found: C, 38.71; H, 4.92; N, 22.66.
Example 54
N-(2-Phenethyl)-N‘- (2-chlorophenvl) thiourea
A solution of 2-chloroaniline (2.55 g, 20 mmol) and 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) in Ν,Ν-dimethylformamide (50 mL) was heated to 100°C for 17 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue was purified by HPLC on silica gel to provide 1.18 g (20%) of the title product as a white solid:
IR (KBr, cm'1) 3378, 3167, 1540, 1499, 1470, 1250, 1060,
758, 685;
iH NMR (300 MHz, DMSO-dg) δ 7.55 (br s, IH), 7.5-7.2 (m,
9H), 5.9 (br s, IH), 3.9 (m, 2H), 2.9 (t, J=7 Hz, 2H) ;
MS (FD) m/e 290 (M+);
UV (EtOH) 245nm (6=16042), 209nm (6=29276).
AP/P/ 9 5 / 0 0 7 2 3 BAD ORIG|NAL A
APO 00 3 88
-65 Anal. Calcd for C15H15N2SCI:
Theory: C, 61.95; H, 5.20; N, 9.63.
Found: C, 61.69; H, 5.28; N, 9.84.
Example., .55.
N-lbenzvl)-Ν' -Γ2-(5-chloro)thiazolyl1 thiourea
A solution of benzyl isothiocyanate (3.0 g, 20 mmol) and 2-amino-5-chlorothiazole (2.69 g, 20 mmol) in Ν,Ν-dimethylformamide (25 mL) was heated at 100eC for 20 h.
The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCI, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue purified ty HPLC on silica gel to provide 0.86 g (15%) of the title product:
mp 162-164eC;
IR (KBr, cm-1) 3154, 3003, 2958, 1588, 1515, 1421, 1231, 1192, 726;
Ih NMR (300 MHz, DMSO-dg) δ 8.8 (br s, IH), 7.45 (s IH),
7.4-7.2 (m, 5H), 4.7 (m, 2H);
MS (El) m/e 283 (M+);
UV (EtOH) 295nm (£=6457), 259 nm (£=5741), 208 nm (£=11042).
AP/P/ 9 5 / 0 0 7 2 3
Example 56
N-.i3-PhenylDropy.il -Nl-J2- (5-chloro) thiazolyl) thiourea 25 A solution of 3-phenylpropyl isothiocyanate (3.54 g, 20 mmol) and 2-amino-5-chlorothiazole (2.69 g, 20 mmol) in N,N-dimethylformamide (50 mL, was heated to 100*0.
After 18 h, the reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous
HCI, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue purified by_
BAD ORIGINAL
APO 0 0 3 8 8
- 66 HPLC on silica gel to provide 0.29 g (5%) of the title product: mp 121-130’C;
IR (KBr, cm1) 3160, 3100, 2949, 1565, 1517, 1493, 698;
!h NMR (300 MHZ, DMSO-d6> δ 10.8 (s, IH), 8.5 (br s, IH),
7.4 (s, IH), 7.3 (m, 5H), 3.5 (m, 2H), 2.6 (t, J=7.7 Hz,
2H), 1.8 (m, 2H);
MS (FD) m/e 311 (M+);
UV (EtOH, 295nm (£=14069), 259nm (£=12092), 205nm (£=27316).
Anal. Calcd for C13H14N3S2CI:
Theory: C, 50.07; H, 4.52; N, 13.47.
Found: C, 50.17; H, 4.51; N, 13.42.
Example 57
N- (2-Phenethvl)-Ν' -(5-tetrazovl) thiourea
A solution of 5-aminotetrazole monohydrate (2.06 g, 20 mmol) and 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) in N,N-dimethylformamide (50 mL) was heated to 100°C for 21 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized twice from ethyl acetate to provide 0.59 g (12%) of impure title product:
AP/P/ 9 5 / 0 0 7 2 3
25 mp 161-177’C;
IR (KBr, cm-1) 3451, 3235, 3148, 1547, 1511, 1169, 697;
1H NMR (300 MHz, DMSO-d6) 8 10.8 (S, IH,, 10.4 (m, IH), 8.6
(br s, IH), 7.2-7.0 (m, 5H), 3.8 tin, 2H), 2.8 (t, J=7 Hz,
2H) t
30 MS (FD) m/e 248 (M+);
UV (EtOH) 258nm (£=13630), 234nm (£=15631) , 204nm (£=15594).
APOΟ Ο 388
- 67 Example 58
Ν-?2-phenethyl) -Ν ‘ - f 2 - (4-methvl-5-acetvl)thiazolyl1 xhifiurfia
A solution of 2-phenethyl isothiocyanate (1.14 g, 7 mmol) and 2-amino-4-methyl-5-acetylthiazole (1.09 g, 7 mmol) in Ν,Ν-dimethylformamide (50 mL) was heated at 100°C for 23 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized twice from ethyl acetate to provide 0.21 g (9%) of the title product:
IR (KBr, cm1) 3314, 3060, 1694, 1610, 1555, 1507, 1372, 1233, 980, 667;
!h NMR (300 MHz, DMSO-dg) 8 12.5(br s, IH), 8.8 (br s, IH),
7.4-7.2 (m, 5H,, 3.8 (m, 2H), 2.9 (t, J=7 Hz, 2H) 2.4 (s,
3H), 2.3 (s, 3H);
MS (FD) m/e 319 (M+);
UV (EtOH, 319nm (£=16944), 230 nm (£=13216), 201 nm (£=18476).
AP/P/ 9 5 / 0 0 7 2 3
Example 59
N-(2-Phenethvl)-N‘-f2-(6-chloro)pvrazinvl) thiourea
A solution of 2-amino-6-chloropyrazine (2.59 g, 20 mmol) and 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) in Ν,Ν-dimethylformamide (50 mL) was heated to 100°C for 35 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue
BAD original
APOOO 388
- 68 purified by HPLC on silica gel to provide 0.23 g (4%) of the title product: mp 194-195°C;
IR (KBr, cm1) 3171, 2932, 1575, 1517, 1465, 1359, 1270,
1169, 707;
!h NMR (300 MHz, DMSO~d6) δ 11.2 (s, IH) , 10.2 (br s, lH),
8.5 (s, 1H), 8.3 (s, IH) , 7.4-7.2 (m, 5H), 3.85-3.75 (m,
2H) , 2.9 (t, J=7 Hz, 2H);
MS (FD) m/e 292 (M+);
UV (EtOH) 328nm (£=12858), 265nm (£=17945), 201nm (£=17746).
Example 60
N- (2-phenbutvl)-Ν’ -J2-thiazolvl1 thiourea A solution of 2-phenbutyl isothiocyanate (3.8 g,
20 mmol) and 2-aminothiazole (2.0 g, 20 mmol) in N,Ndimethyl-formamide (50 mL) was heated at 100°C for 26 h.
The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl ether to provide 2.3 g (39%) of the title product: mp 105-107°C
IR {KBr, cm-1) 3171, 2932, 1575, 1517, 1465, 1359, 1169, 1064, 707;
2H NMR (300 MHz, DMSO-d6) δ 11.5 (br s, IH), 9.7 (br s,
IH), 7.4-7.1 (m, 7H), 3.6 (m, 2H), 2.6 (m, 2H), 1.6 (m,
4H) ;
MS (FD) m/e 291 (M+);
UV (EtOH) 288nm (£=19013), 256 nm (£=10681), 203 nm (£=18908).
AP/P/ 9 5 / 0 0 7 2 3 original
APO Ο Ο 3 8 8 : 69 Anal. Calcd for C14H17N3S2:
Theory: C, 57.70; H, 5.88; N, 14.42.
Found: C, 57.60; H, 6.08; N, 14.56.
Example 61
N- (2 - Phenethyl ) -N' - f2 - (4.- (3-nitrQ)phenvL)Xhiazolvll· thiourea
A solution of 2-phenethyl isothiocyanate (0.74 g, 4.5 mmol) and 2-amino-4-[(3-nitro)phenyl]-thiazole (1.0 g, 4.5 mmol) in N, Ν-dimethylformamide (50 mL) was heated to
100°C for 120 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue purified by HPLC on silica gel to provide 0.07 g (4%) of the title product: mp 192-196°C;
IR (KBr, cm1) 3165, 3023, 1571, 1517, 1352, 1217, 1166;
NMR (300 MHz, DMSO-d6) 5 11.7 (br s, IH), 9.0 (br s,
IH), 8.6 (s, IH), 8.2 (m, 2H), 7.75 (s, IH), 7.6 (t, J=6 Hz, IH), 7.4-7.2 (m, 5H), 3.8 (m, 2H), 2.95 it, J=6 Hz,
2H) ;
ΛΡ/Ρ/ 9 5 / 0 0 7 2 3
MS (FD) m/e 384 (M+);
UV (EtOH) 286nm (£=21349), 264nm (£=22766), 237nm
(£=18307), 202nm (£=28514) .
Anal. Calcd for C18H16N4S2O2:
Theory : C, 56.23; H, 4.19; N, 14.57.
Found: C, 56.12; H, 4.24; N, 14.47.
BAD ORIGINAL £)»
ΑΡ ο Ο Ο 3 β 8
- 70 Example 62
Ν- (n-PropylJ.:H' :-.12.- (,5.- chi or Qthiazoyl) I thiourea
A solution of 2-amino-5-chlorothiazole (2.69 g, 20 mmol) and n-propyl isothiocyanate (2.0 g, 20 mmol, in
N, N-dimethylformamide (50 mL) was heated to 100°C for 19 h.
The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue purified by HPLC on silica gel to provide 0.17 g (4%) of the title product: mp 128-133°C;
IR (KBr, cm-1) 3170, 2958, 1560, 1487, 1187, 691;
1H nmr (300 MHz, DMSO-de) δ 11.5 (br s, IH,, 8.4 (br s,
IH) , 7.4 (s IH), 3.4 (m, 2H, , 1.6 (m, 2H), 0.95 (t, J=7 Hz,
3H);
MS (FD) m/e 235 (M+);
UV (EtOH) 294nm (6=12928), 259nm (6=10257), 204nm (6=16979). Anal. Calcd for C7H10N3S2CI:
Theory: C, 35.66; H, 4.28; N, 19.82.
Found: C, 35.85; H, 4.19; N, 19.78.
Example ¢3
N- (2-phenethyl) -Μ',-ΙΣ- (4- (2',2 ’-diphenvl-2 1 cvanolethvU thiazovll thiourea
A solution of 2-amino(4-(2 *,2'-diphenyl-2'cyano)ethyl) thiazole (0.91 g, 3 mmol) and 2-phenethyl isothiocyanate (0.49 g, 3 mmol) in Ν,Ν-dimethylformamide (50 mL) was heated to 100°C for 91 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated
AP/P/ 9 5 / 0 0 7 2 3 bad ORIGINAL $
AP000388
- 71 and the residue purified by HPLC on silica gel to provide
0.28 g (20%) of the title product:
IR (KBr, cm'1) 3179, 3024, 2238, 1562, 1250, 698;
1H NMR (300 MHZ, DMSO-d^) 8 11.5 (s, IH) , 10.4 (br S, IH) ,
7.5-7.2 (m, 15H,, 6.6 (s, IH), 3.85 (s, 2H), 3.8 (m, 2H),
2.8 (t, J=7 Hz, 2H);
MS (FD) m/e 468 (M+);
UV (EtOH) 292nm (£=12023), 259nm (£=5862), 202 nm (£=25516). Anal. Calcd for C27H24N4S2:
Theory: C, 69.20; H, 5.16; N, 11.95.
Found: C, 69.05; H, 5.33; N, 11.76.
Example 64
Nt 1.2- 11-cvclohexenylLethvl·) -Ν' - f2-benzothiazolyl 1 thiourea
A solution of 2-(1-cyclohexenyl)ethyl isothiocyanate (3.3 g, 20 mmol, and 2-aminobenzothiazole (3.0 g, mmol) in Ν,Ν-diraethylformamide (50 mL) was heated at 100°c for 17.5 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acetate to provide 2.57 g (40%) of the title product:
mp 185-186°C;
IR (KBr, cm'1) 3179, 3044, 2921, 2830, 1556, 1523, 1441, 1196;
!h NMR (300 MHz, DMSO-d6) d 11.8 (br s, IH) , 10.2 (br s,
IH), 8.0-7.2 (m, 4H), 5.45 (s, IH), 3.65 (m, 2H), 2.3 (t,
J=7 Hz, 2H), 1.9 (m, 4H), 1.5 (m, 4H);
MS (FD) m/e 317 (M+,;
UV (EtOH) 287nm (£=20679), 201 nm (£=25939).
AP/P/ 9 5 / 0 0 7 2 3 bad original £
APO 0 0 3 8 8
- 72 Anal. Calcd for C16H19N3S2:
Theory: C, 60.53; H, 6.03; N, 13.24.
Found: C, 60.29; H, 5.94; N, 13.49.
Example 65
N- (2-phenethvl) -Ν' -.12-.14-ethvl} thiazolvll thiourea
A solution of 2-phenethyl isothiocyanate (1.63 g, 10 mmol) and 2-amino-4-ethylthiazole (1.28 g, 10 mmol, in N, N-dimethyl formamide (50 mL) was heated at 100°C for 23
h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acetate to provide 0.84 g (29%, of the title product: mp 145-146°C;
IR (KBr, cm-1, 3199, 3049, 2962, 1591, 1275, 685;
!h nmr (300 MHz, DHSO-d$) 6 11.5 (br s, IH), 9.8 (br s,
IH), 7.4-7.2 (m, 5Η), 6.6 (s, IH,, 3.8 (m, 2Η), 2.9 (t, J=7
Hz, 2H), 2.45 (q, J=7 Hz, 2H), 1.1 (t, J=7 Hz, 3H) ;
MS (FD) m/e 291 (M+);
UV (EtOH) 292nm (£=19382), 257 nm (£=10362), 202 nm (£=20282).
Anal. Calcd for C14H17N3S2:
Theory: C, 57.70; H, 5.88; Ν, 14.42.
Found: C, 57.47; H, 5.91; N, 14.51.
Example 66
1.: I (2-benzoLhiazolynthiocarbamovl). imidazole
A solution of 1,1’-thiocarbonyldiimidazole (8.9 g, 50 mmol) and 2-aminobenzothiazole (7.5 g, 50 mmol) in
AP/P/ 9 5 / 0 0 7 2 3
SAD ORIGINAL A
APO Ο Ο 3 8 8
- 73 acetonitrile (125 mL, was stirred at room temperature for 20 h. The resulting precipitate was collected by filtration to provide 5.75 g (44%, of the title product:
IR (KBr, cm1) 3199, 3049, 2962, 1628, 1461, 738;
1H NMR (300 MHz, DMSO-dg) δ 8.85 (s, IH), 8.1 (br s, IH),
7.9-7.0 (m, 6H);
MS (FD) m/e 261 (M+);
UV (EtOH) 3S6nm (£=13072), 305 nm (£=11556), 213 nm (£=35893).
Anal. Calcd for C11H8N4S2:
Theory: C, 50.75; H, 3.10; N, 21.52.
Found: C, 50.50; H, 3.02; N, 21.49.
Example ¢7
N.-.12 - (2-chlQrophenvl.) ethvl 1 -Ν' - Γ2-benzothiazolyl 1 thiourea
A solution of 1-I(2-benzothiazolyl)thiocarbamoyl] imidazole (2.1 g, 8 mmol) and 2-(2chlorophenyl,-ethylamine (1.25 g, 8 mmol, in Ν,Νdimethylformamide (30 mL) was stirred at 100°C for 1.5 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 1.6 g (57%) of the title product:
IR (KBr, cm-1) 3181, 3050, 1587, 1527, 1231, 753;
!h NMR (300 MHz, DMSO-dg) δ 11.9 (br s, IH), 10.0 (br s,
IH), 7.8-7.2 (m, 8H,, 3.95 (m, 2H), 3.1 (t, J=7 Hz, 2H);
MS (FD) m/e 347 (M+);
UV (EtOH) 301nm (£=23050), 202 nm (£=30924,.
AP/P/ 9 5 / 0 0 7 2 3
APO00388
- 74 Example 68
N-f2 - (3-chloroohenvl)ethyll-N1.-.12--benzothiazolyl 1 thiourea
A solution of 1-[(2-benzothiazolyl)thiocarbamoyl] imidazole (1.04 g, 4 mmol) and 2-(35 chlorophenyl)ethylamine (0.63 g, 4 mmol) in N,Ndimethylformamide (15 mL) was stirred at 100°C for 1 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 0.88 g (63%) of the title product:
IR (KBr, cm-1) 3180, 2997, 1569, 1527, 1209, 755;
1h NMR (300 MHz, DMSO-dg) δ 11.9 (br s, IH,, 10.1 (br s,
IH), 7.8-7.2 (m, 8H), 3.9 (m, 2H), 3.0 (t, J=7 Hz, 2H) ;
MS (FD) m/e 347 <M+);
UV (EtOH) 301nm (€=25367), 202 nm (€=31735).
Anal. Calcd for C16H14N3S2CI:
Theory: C, 55.24; H, 4.06; N, 12.08.
Found: C, 55.05; H, 4.05; N, 12.03.
Example 69
N- f 2 - (4 - chlorophenvl) ethvl 1 -N- f 2-benzothiazolyl 1 thiourea
A solution of 1-[(2-benzothiazolyl)thiocarbamoyl] imidazole (1.04 g, 4 mmol) and 2-(4chlorophenyl)ethylamine (0.63 g, 4 mmol) in N,Ndimethylformamide (15 mL) was stirred at 100°C for 1 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 0.89 g (64%) of the title product:
IR (KBr, cm1) 3180, 2997, 1569, 1527, 1257, 755;
!h NMR (300 MHz, DMSO-dg) δ 12.0 (br s, IH), 10.0 (br s,
IH), 7.9-7.2 (m, 8H), 3.85 (m, 2H), 2.95 (t, J=7 Hz, 2H);
ϊ £ L υ υ / s 6 Zd/dV
APO00388
-75 UV (EtOH, 301nm (ε=25731,, 218nm (£=29376), 202 nm (€=28033) .
Anal. Calcd for C16H14N3S2CI:
Theory: C, 55.24; H, 4.06; N, 12.08.
Found: C, 55.27; H, 4.02; N, 12.10.
ExamplaJd
Ν- I 2 - (2-methoxvphenvl, ethvl I -N'-f 2-benzothiazolyl 1 thiourea
A solution of 1-[(2-benzothiazolyl)10 thiocarbamoyl] imidazole (1.04 g, 4 mmol) and 2-(2methoxyphenyl)ethylamine (0.62 g, 4 mmol) in Ν,Νdimethyl formamide (15 mL) was stirred at 100*C for 1 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 0.9 g (66%) of the title product:
IR (KBr, cm'1) 3180, 1672, 1539, 1437, 1202, 1137, 783;
!h NMR (300 MHz, DMSO-dg) δ 12.0 (br β, IH), 10.0 (br s,
IH,, 7.9-7.0 (m, 8Η), 3.85 (m, 2H),Ύ.75 (s, 3H), 2.9 (t,
J=7 Hz, 2Η);
MS (FD) m/e 343 (M+);
UV (EtOH) 301nm (€=25894), 218nm (€=28357), 202 nm (€=32552) .
Anal. Calcd for C17H17N3OS2:
Theory: C, 59.45; H, 4.99; N, 12.23.
Found: C, 59.70; H, 5.01; N, 11.99.
Example 71 (2-methQXVPhenvl) ethvl1-N1 - f2-benzothiazolyl] thiourea
A solution of 1-((2-benzothiazolyl)30 thiocarbamoyl] imidazole (1.04 g, 4 mmol) and 2-(3AP/P/ 9 5 / 0 0 7 2 3
BAD original £
AP Ο Ο Ο 3 8 8
- 76 methoxyphenyl) ethyl-amine (0.62 g, 4 mmol) in N,Ndimethylformamide (15 mL) was stirred at 100°C for 1 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 0.77 g (56%) of the title product:
IR (KBr, cm’1) 3180, 1670, 1543, 1479, 1205, 1136, 718;
1H NMR (300 MHz, DMSO-d6) δ 11.9 (br s, IH), 10.05 (br s, IH), 7.9-6.8 (m, 8H), 3.87 (m, 2H), 3.75 (s, 3H), 2.95 (t, J=7 Hz, 2H);
MS (FD) m/e 343 (M+);
UV (EtOH) 301nm (€=24893), 216nm (€=28250), 203 nm (€=33504).
Anal. Calcd for C17H17N3OS2:
Theory: C, 59.45; H, 4.99; N, 12.23.
Found: C, 59.36; H, 5.02; N, 12.00.
Example 72
Ν-Γ2-(4-me thoxyphenyl)ethvll-N‘-f2-benzothiazolvll thiourea
A solution of 1-[(2-benzothiazolyl) 20 thiocarbamoyl] imidazole (1.04 g, 4 mmol) and 2-(4methoxyphenyl)ethylamine (0.62 g, 4 mmol) in N,Ndimethylformamide (15 mL) was stirred at 100®C for 1 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 0.85 g (62%) of the title product:
IR (KBr, cm’1) 3162, 1610, 1572, 1255, 1208, 1106, 761;
!h NMR (300 MHz, DMSO-dg) δ 11.9 (br s, IH), 10.05 (br s,
IH), 7.9-6.8 (m, 8H), 3.85 (m, 2H), 3.75 (s, 3H), 2.9 (t,
J = 7 Hz, 2H);
MS (FD) m/e 343 (M+);
AP/P/ 9 5 / 0 0 7 2 3 bad original
APO00388
- 77 UV (EtOH) 301nm (£=22113), 218nm (£=23878), 201 nm (£=28098).
Anal. Calcd for C17H17N3OS2:
Theory: C, 59.45; H, 4.99; N, 12.23.
Found: C, 59.33; H, 5.06; N, 12.04.
Example. 7J.
1-f(2-f4.5-dimethvl1thiazolvll.thiocarbamoyl1 imidazole
A solution of 1.1'-thiocarbonyldiimidazole (1.8 g, 10 mmol), 2-amino-4,5-dimethylthiazole hydrochloride (1.65 g, 10 mmol) and triethylamine (1.01 g, 10 mmol) in acetonitrile (40 mL) was stirred at room temperature for 7
h. The solvent was removed in vacuo to afford crude of the 15 title product as a yellow solid used in the next step without purification.
Example 74
Mr 12 - (2 - Chlorophenvl) ethvl 1-M f 2 - (4. 5 -dimethyl) thiazolyl 1 20 thiourea
A solution of l-ί(2-[4,5-dimethyl]thiazolyl) thio-carbamoyl] imidazole (10 mmol) and 2-(2-chlorophenyl)ethylamine (1.55 g, 10 mmol) in N,N-dimethylformamide (30 mL) was stirred at 90°C for 1 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acetate to provide 2.1 g (65%) of the title product:
IR (KBr, cm-1) 3171, 3013, 1583, 1549, 1510, 1216, 759;
AP/P/ 9 5 / 0 0 7 2 3
bad ORIGINAL
APOΟ Ο 388 f w *
- 78 !h NMR (300 MHz, EWSO-d6) δ 11.45 (br s, IH), 9.75 (br s, IH) , 7.5-7.2 (m, 4H), 3.85 (m, 2H), 3.05 (t, J=7 Hz, 2H) ,
2.2 (s, 3H), 2.05 (s, 3H);
MS (FD) m/e 325 (M+);
UV (EtOH, 297nm (£=9209), 257nm (£=5133), 201 nm (£=14635).
Example 75
Ν-ί 2 - (3-chlorophenvl)ethvl1-N'-f 2- (4,5-dimethyl)thiazolyl1 thiourea
A solution of 1-[(2-[4,5-dimethyl]thiazolyl) thio-carbamoyl] imidazole (10 mmol) and 2-(3-chlorophenyl) ethylamine (1.55 g, 10 mmol) in Ν,Ν-dimethylformamide (30 mL) was stirred at 90°C for 1 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystaiiized from ethyl acetate to provide 2.2 g (67%) of the title product:
IR (KBr, cm-1) 3182, 3018, 1584, 1549, 1511, 1215, 788;
1h NMR (300 MHz, DMSO-d6) δ 11.45 (br s, IH,, 9.8 (br s,
IH), 7.4-7.2 (m, 4H), 3.85 (m, 2H), 2.9 (t, J=7 Hz, 2H),
2.2 (s, 3H), 2.05 (s, 3H);
MS (FD) m/e 325 (M+);
UV (EtOH) 297nm (£=6543), 257nm (£=3650,.
Anal. Calcd for C14H16N3S2CI:
Theory: C, 51.60; H, 4.95; N, 12.89.
Found: C, 51.73; H, 4.99; N, 13.16.
AP/P/ 9 5 / 0 0 7 2 3
BAD ORIGINAL
APO 00 3 88
-79 Example 76
K- f 2 - (2 -methoxvphenvllethvl 1 -N' - f 2 - (4.5-dimethyl) thiazolyl 1 thiourea
A solution of l-[ (2-(4,5-dimethyl] thiazolyl) thio-carbamoyl] imidazole (47) (10 mmol) and 2-(2methoxyphenyl)ethylamine (1.51 g, 10 mmol) in Ν,Νdimethylformamide (30 mL) was stirred at 90*C for 1 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acetate to provide 1.9 g (65%) of the title product: mp 178-180°C;
IR (KBr, cm1) 3175, 2998, 1598, 1495, 1213, 760, 707;
ΣΚ NMR (300 MHz, DMSO-dg) d 11.4 (br s, IH), 9.75 (br s,
IH· , 7.25-6.8 (m, 4H), 3.8 (s, 3H), 3.78 (m, 2H), 2.87 (t. J=7 Hz, 2H), 2.2 (s, 3H), 2.05 (s. 3H);
MS (FD). m/e 321 (M+) ;
UV (EtOH) 297nm (6=18573), 258nm (6=10587), 202 nm (6=28862) .
Anal. Calcd for C15H19N3OS2:
Theory: C, 56.04; H, 5.96; N, 13.09.
Found: C, 56.29; H, 6.19; N, 13.27.
Example 77
N-J2 - (3-methQXVPhenvl)ethvll-N'-f2-(4.5-dimethyl) thiazolyl) thiourea
A solution of 1-( (2-(4,5-dimethyl]thiazolyl) thiocarbamoyl] imidazole (10 mmol) and 2-(3methoxyphenyl)ethylamine (1.51 g, 10 mmol, in N,NAP/P/ 9 5 / 0 0 7 2 3
AP000388 .<·*>
- 80 reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acetate to provide 2.2 g (69%, of the title product:
mp 146-148°C;
IR (KBr, cm’1) 3179, 3035, 1587, 1551, 1214, 701, 682;
ΧΗ NMR (300 MHz, DMSO-d6) 6 11.45 (br s, IH, , 9.8 (br s',
IH), 7.25-6.8 (m, 4H,, 3.8 (m, 2H,, 3.75 (s, 3H,, 2.85 (t,
J=7 Hz, 2H), 2.2 (s, 3H) , 2.05 (s, 3H,;
MS (FD> m/e 321 (M+) ;
UV (EtOH) 297nm (£=16992), 258nm (£=9639), 202 nm (£=27993). Anal. Calcd for C15H19N3OS2:
Theory: C, 56.04; H, 5.96; N, 13.09.
Found: C, 56.01; H, 5.96; N, 13.30.
Example 78
Ν-.Γ2- (4-jnethQxyDhenvlIethyirrNl--f2 - (4,5-dimethyl) thiazolyl 1 thiourea
A solution of 1-((2-[4,5-dimethyl)thiazolyl) thiocarbamoyl) imidazole (10 mmol) and 2-(4methoxyphenyl)ethylamine (1.51 g, 10 mmol) in N,Ndimethylformamide (30 mL) was stirred at 90°C for 1 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acetate to provide 2.2 g (69%) of the title product: mp 178-180°C;
IR (KBr, cm-1) 3174, 3024, 1590, 1552, 1214, 688;
AP/P/ 9 5 / 0 0 7 2 3 bad ORIGINAL
AP Ο Ο Ο 3 8 8
- 81 !η NMR (300 MHz, DMS0-d6) δ 11.45 (br s, 1Η), 9.8 (br s,
1Η) , 7.2(d, J=8 Hz, 2H), 6.85 (d, J=8 Hz, 2H) , 3.78 (m,
2H), 3.75 (s, 3H), 2.85 (t, J=7 Hz, 2H), 2.2 (s, 3H,, 2.05 (s, 3H) ;
MS (FD) m/e 321 (M+>;
UV (EtOH) 297nm (£=8102), 258nm (£=4813), 223 nm (£=6614).
Example 72
M-(2-phenethy 11 -·Μ·-(5-.(3-methvllisothiazolvl) thiourea
A solution of 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) and 5-amino-3-methylisothiazole (3.0 g, 20 mmol) in N, N-dimethylf ormamide (30 mL) was heated at 100°C 24 h, the reaction was cooled to room temperature and poured into ethyl acetate, washed with water, IN aqueous
HCI, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acetate to provide 5.5 g (100%) of the title product:
mp 213-216°C;
IR (KBr, cm-1) 3188, 2744, 1593, 1525, 1495, 1423, 1313, 1248, 829, 777, 752, 705, 670, 522;
!h NMR (300 MHz, OMSO-άζ) δ 9.3 (br s, IH) , 7.4-7.2 (m,
5H), 6.35 (br s, IH), 3.7(m, 2H), 2.9 (t, J=7 Hz, 2H,, 2.45 (s. 3H);
MS (FD, m/e 278 (M+);
UV (EtOH) 286nm (£=12263), 247 nm (£=14257), 206 nm (£=27381) .
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- 82 Example. &Q l-f(2-f6-fluoro1 benzothiazolyl) thiocarbamovn imidazole
A solution of 1,1'-thiocarbonyldiimidazole (17.8 g, 100 mmol) and 2-amino-6-fluorobenzothiazole (16.8 g, 100 mmol) in acetonitrile (700 mL) was stirred at room temperature for 20 h, then at 40°C for 6 h. The resulting precipitate was collected by filtration to provide 19.5 g (70%) of the title product:
IR (KBr, cm’1) 3200, 3050, 2558, 1595, 1560, 1461, 1331,
1216, 1088, 1040, 948, 740, 648, 627;
!h NMR (300 MHz, ϋΜΣΟ-άζ) 5 12.0 (br s, IH, , 8.85 (s, IH) ,
8.1 (br s, IH), 7.9-7.0 (m, 4H);
MS (FD) m/e 279 (M+H) ;
UV (EtOH) 364nm (£=7372), 306 nm (£=13593), 213 nm lo (£=31325).
Anal. Calcd for C11H7N4S2F:
Theory: C, 47.47; H, 2.54; N, 20.13.
Found: C, 47.72; H, 2.66; N, 20.09.
Example 81
Ν- Γ2-(2-chlorophenvl)ethvl)-N‘-(2-f6-fluorolbenzothiazolvl) thiourea
A solution of l-[(2-[6-fluoro]benzothiazolyl)thio-caibamoyl] imidazole (2.1 g, 8 mmol) and 2-(2-chloro25 phenyl) ethylamine (1.25 g, 8 mmol) in Ν,Ν-dimethylformamide (30 mL) was stirred at 100°C for 1.5 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 1.6 g (57%) of the title product:
mp 188-189°C;
£ 2 L 0 0 / ς 6 /d/dV
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- 83 IR (KBr, cm1) 3166, 3014, 1560, 1538, 1460, 1217, 1198, 853 ;
NMR (300 MHz, DMSO-dg) d 11.6 (br s, IH,, 9.8 (br s,
IH), 7.9-7.2 (m, 7H), 3.9 (m, 2H), 3.1 (t, J=7 Hz, 2H);
MS (FD) m/e 365 (M*);
UV (EtOH) 301nm (£=22535), 216nm (£=27344), 201 nm (£=28624) .
Anal. Calcd for C16H13N3S2CIF:
Theory: C, 52.53; H, 3.58; N, 11.49.
Found: C, 52.79; H, 3.72; N, 11.76.
Example. .82
N-f 2- (3-chloroDhenvl) ethvl) -N‘- (2-f 6-f luoro) benzothiazolyl) thiourea
A solution of 1-I (2-[6-fluoro]benzothiazolyl,thiocarbamoyl] imidazole (2.1 g, 8 mmol) and 2-(3chlorophenyl)ethylamine (1.25 g, 8 mmol) in N,N-dimethylformamide (30 mL) was stirred at 100°C for 1.5 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 1.6 g (57%) of the title product:
: mp 193-194°C;
IR (KBr, cm1) 3171, 3015, 1557, 1526, 1460, 1229, 1201, 866;
NMR (300 MHz, DMSO-d6) d 11.9 (br s, IH), 9.9 (br s.
IH), 7.9-7.2 (m, 7H), 3.85 (m, 2H), 3.0 (t, J=7 Hz, 2H);
MS (FD) m/e 365 (M+,;
UV (EtOH, 301nm (£=24232), 217nm (£=30020), 201 nm (£=31875) .
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- 84 Anal. Calcd for C16H13N3S2CIF;
Theory: C, 52.53; H, 3.58; N, 11.49.
Found: C, 52.50; H, 3.67; N, 11.38.
Example 83
N-L2z 14-chlorophenvl)ethvll-N1 - (2-f 6-fluoro 1 benzothiazolyl) thiourea
A solution of l-[(2-I6-fluoro)benzothiazolyl,thio-carbamoyl) imidazole (2.1 g, 8 mmol) and 2-(4-chloro10 phenyl)ethylamine (1.25 g, 8 mmol) in Ν,Ν-dimethylformamide (30 mL) was stirred at 100°C for 1.5 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 1.6 g (57%, of the title product:
: mp 217-218°C;
IR (KBr, cm*1) 3168, 3033, 1559, 1532, 1491, 1462, 1230. 1143, 809;
1H NMR (300 MHz, DMSO-d6) d 11.85 (br s, IH), 9.8 (br s, IH), 7.9-7.2 (m, 7H), 3.85 (m, 2H) , 2.95 (t, J=7 Hz, 2H) ;
MS (FD, m/e 365 (M+);
UV (EtOH) 301nm (£=24527), 220nm (£=31031).
Anal. Calcd for C16H13N3S2CIF;
Theory: C, 52.53; H, 3.58; N, 11.49.
Found: C, 52.80; H, 3.70; N, 11.34.
Example 84
N-12 - [2-methoxyphenvl) ethyl] -N‘ -(2-(6iluoro)benzothiazolyl) thiourea A solution of 1-[(2-16-fluoro]benzothiazolyl)30 thiocarbamoyl] imidazole (2.1 g, 8 mmol) and 2-(2-methoxyphenyl)ethylamine (1.25 g, 8 mmol) in Ν,Ν-dimethylformamide
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- 85 (30 mL) was stirred at lOO’C for 1.5 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 1.6 g (57%) of the title product:
: mp 208-209°C;
IR (KBr, cm4) 3168, 3034, 1561, 1536, 1462, 1242, 1198, 852;
1h nmr (300 MHz, DMSO-dg) d 11.85 (br s, 1H) , 9.8 (br s, 1H), 7.9-7.0 (m, 7H), 3.85 (m, 2H), 3.8 (s, 3H), 2.9 (t,
J=7 Hz, 2H);
MS (FD) m/e 361 (M+);
UV (EtOH) 300nm (£=24273), 218nm (£=28369), 201 nm (£=34036) .
Anal. Calcd for C17H3.6N3OS2CF:
Theory: C, 56.49; H, 4.46; N, 11.63.
Found: C, 56.56; H, 4.59; N, 11.66.
Examole 85
N-f 2- (3-methoxvphenvl)ethvl1 -N'- (2-ί 62G fluoro)benzothiazolyl) thiourea
A solution of 1-((2-[6-fluoro]benzothiazolyl)thiocarbamoyl] imidazole (2.1 g, 8 mmol) and 2-(3-methoxyphenyl)ethylamine (1.25 g, 8 mmol) in Ν,Ν-dimethylformamide (30 mL) was stirred at 100*C for 1.5 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 1.6 g (57%) of the title product:
mp 190-192°C;
_IR (KBr, cm4) 3050, 1536, 1460, 1302,1221, 1060, 674;
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- 86 XH NMR (300 MHz, DMSO-dg) d 11.9 (br s, IH), 9.9 ibr s, IH), 7.9-7.0 (m, 7H), 3.85 (m, 2H) , 3.75 (s, 3H>, 2.95 (t, J=7 Hz, 2H);
MS (FD) m/e 361 (M+);
UV (EtOH) 301nm (£=24608), 218nm (£=28535), 201 nm (£=37337).
Anal. Calcd for C17H16N3OS2CF:
Theory: C, 56.49; H, 4.46; N, 11.63.
Found: C, 56.21; H, 4.54; N, 11.40.
Example 86
N-I2r (4-jnethoxyphenvl)ethvl1 -N· - (2-f6fluorolbenzothiazolyl) thiourea A solution of 1-((2-[6-fluorolbenzothiazolyl)thio-carbamoyl] imidazole (54) (2.1 g, 8 mmol) and 2-(4methoxy-phenyl)ethylamine (1.25 g, 8 mmol) in Ν,Νdimethylformamide (30 mL) was stirred at 100°C for 1.5 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 1.6 g (57%) of the title product:
: mp 203-204.5°C;
IR (KBr, cm’1) 3001, 1561, 1539, 1458, 1251, 860, 818; χΗ NMR (300 MHz, DMSO-dg) d 11.85 (br s, IH), 9.85 (br s, IH), 7.9-6.9 (m, 7H), 3.85 (m, 2H), 3.75 (s, 3H,, 2.9 (t, J=7 Hz,. 2H) ;
MS (FD) m/e 361 (M+);
UV (EtOH) 301nm (£=23562), 222 nm (£=28328).
.Anal. Calcd for Ci7HigN3OS2CF:
Theory: C, 56.49; H, 4.46; N, 11.63.
Found: C, 56.70; H, 4.42; N, 11.79.
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- 87 Example. £.7.
1-f(2-f5-chlorolthiazolvl)thiocarbamovll imidazole
A solution of 1,1‘-thiocarbonyldiimidazole (25 5 g, 140 mmol) and 2-amino-5-chlorothiazole (18.8 g, 140 mmol) in acetonitrile (300 mL) was stirred at room temperature for 23 h. The resulting precipitate was collected by filtration to provide 21.2 g (62%) of the title product:
1H NMR (300 MHz, DMSO-dg) δ 9.5 (S, IH), 8.2 (S, IH), 7.6 (s, IH), 7.5 (S, IH);
MS (FD) m/e 176 (M+-C3H3N2)·
Example 88
N-f 2- (2-chlorophenvl)ethvl1-N‘-Γ2-(5-chloro)thiazolvlI ihiourea
A solution of 1-((2-{5-chloroJthiazolyl)thiocarbamoylj imidazole (0.68 g, 2.8 mmol, and 2-(2-chlorophenyl)ethylamine (0.43 g, 2.8 mmol) in N,N20 dimethylformamide (15 mL) was stirred at 100*C for 1 h.
The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCI, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acetate to provide 0.68 g (73%, of the title product: mp 172-174°C;
IR (KBr, cm1) 3318, 2873, 1606, 1526, 1513, 1436, 1351, 1237, 747;
Ih NMR (300 MHz, DMSO-dg) δ 10.7 (br s, IH) , 8.5 (br s,
IH,, 7.4 (s, IH), 7.4-7.2 (m, 4H,, 3.8 (m, 2H,, 2.9 (t, J=7 Hz, 2H);
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- 88 MS (FD) m/e 331 (M+);
UV (EtOH) 295nm (£=11804), 259 nm (£=10397), 202 nm (£=27067).
Anal. Calcd for C12H11N3S2CI2:
Theory: C, 43.38; H, 3.34; N, 12.65.
Found: C, 43.61; H, 3.57; N, 12.57.
Example 82
N- f 2- (3-chlorophenvlLethvll-N.1.-12- (5-chloro) thiazolyl 1 ie rhicuraa.
A solution of 1-[(2-[5-chloro]thiazolyl)thiocarbamoyl] imidazole (1.22 g, 5 mmol) and 2-(3-chlorophenyl)ethylamine (0.78 g, 5 mmol) in N,N-dimethylformamide (20 mL) was stirred at 100°C for 1 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl ether to provide 0.9 g (54%) of the title product:
mp 154-155°C;
IR (KBr, cm*1) 3178, 3044, 1557, 1520, 1458, 1346, 1196,
784, 755;
1H NMR (300 MHz, DMSO-dg) δ 11.6 (br s, IH), 8.4 (br s,
IH), 7.4 (s, IH), 7.4-7.2 (m, 4H), 3.7 (m, 2H), 2.8 (t, J=7
Hz, 2H) ;
MS (FD) m/e 331 (M+);
UV (EtOH) 296nm (£=14281), 259 nm (£=12090), 205 nm (£=29809).
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- 89 Example-SLQ
Ν-Γ2-(4-chlorophenvl) ethyl1-N*-f2-(5-chloro)thiazolvl) thiourea
A solution of 1-[(2-[5-chloro]thiazolyl)thiocar5 bamoylj imidazole (1.22 g, 5 mmol) and 2-(4-chlorophenyl)ethylamine (0.78 g, 5 mmol) in Ν,Ν-dimethylformamide (20 mL) was stirred at 100*C for 1 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acetate to provide 1.1 g (66%) of the title product:
mp 178-180’C?
IR (KBr, cm1) 3180, 2927, 1610, 1536, 1492, 1325, 1256,
1181, 1088, 1014, 811, 747, 643, 508;
ΣΗ NMR (300 MHz, DMSO-dg) δ 11.6 (br s, IH), 8.4 (br s,
IH), 7.4 (s, IH), 7.32 (d, J=8 Hz, 2H), 7.22 (d, J=8 Hz,
2H,, 3.7 (m, 2H), 2.8 (t, J=7 Hz, 2H);
MS (FD, m/e 331 (M+);
UV (EtOH, 295nm (£=13675), 259 nm (£=12330), -202 nm (£=27524) .
Anal. Calcd for C3.2H11N3S2CI2:
Theory: C, 43.38; H, 3.34; N, 12.65.
Found: C, 43.61; H, 3.46; N, 12.85.
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- 90 Example 31
Ν- (2 - (1-methvl)-2-PvrrolvlethvlJ -Ν'_- (2-thiazolvl) thiourea
An isothiocyanate of 2-(2-aminoethyl)-1methylpyrrole was prepared according to Αηη 657, 104-107 (1962). 3H-NMR (CDCI3) 52.95 (t, 2H) , 3.55 (s, IH), 3.65 (t, 2H) , 5.9-5.95 (m, IH), 6.05 (t, IH) , 6.55 (t, 1H>. This isothiocyanate was dissolved in DMF (4 ml). To this solution was added 200 mg (2 mmol) of 2-aminothiazole and the solution was heated at 100°C for about 16 h. EtOAc was added and the organic phase was washed with sat. NH^Clsolution and brine. After drying (Na2SO4), the product was purified on a silica gel column, using EtOAc/Hexane 1:1, as eluent. This gave almost pure titled product.
Recrystallization from toluene/hexanes gave 150 mg of the titled product.
Mp: 183-184°C (dec).
^-H-NMR (DMSO-dg) δ 2.86 (t, 2H) , 3.55 (s, 3H) , 3.75 (q,
2H), 5.85-5.90 (m. 2H), 6.62 (s, IH,, 7.09 (d, IH), 7.36 (d, IH), 9.74 (broad s, IH), 11.65 (broad s, IH).
13C-NMR (DMSO-dg) δ 25.03, 33.31, 43.92, 106.24, 106.31,
112.03, 121.55, 129.33, 136.71, 161.68, 178.25.
Example 92
N-(2-(1-pjperazinvlethvl))-Ν' -(2-thiazolvl)thiourea
1.78 g Thiocarbonyldiimidazole (10 mmol, was added to a solution of 1.29 g 1-(2-aminoethyl)piperazine (10 mmol) in 5 ml methylene chloride at 0°C. The reaction mixture was warmed to room temperature, and stirred for 30 minutes. The methylene chloride was evaporated, and 40 ml dimethylformamide together with 10.01 g 2-aminothiazole were added. The mixture was stirred 17 h at 100°C. The
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- 91 product was purified by chromatography on a silica gel column eluted with mixtures of methanol and chloroform. Crystallization of the salt with oxalic acid gave further purification.
^K-NMR (oxalate in D2O,: 2.8-3.7 ppm (m), 6.75 ppm (d), 7.1 ppm (d,.
Example 9.3
N- (2- (2-chloro)phenethyl)-Ν' -(2-thiazolvl) thiourea
1? Thiocarbonyldiimidazolide (980 mg, 5.5 mmole) was dissolved in 20 ml methylene chloride. To the solution was added dropwise 2-chlorophenethylamine (0.69 ml, 5 rrmole) in 20 ml methylene chloride at 0eC. After reaction for 3 0 min at 0°C, it was warmed up to room temperature, and then concentrated to small volume in vacuo. To the residue was added 20 ml DMF and 2-aminothiazole (700 mg, 7 mmole) . It was kept at 100°C for 3 hours. After cooling to room temperature, it was poured into 1 N HCl solution (100 ml) and extracted with ethyl acetate (2 x 100 ml); the organic phase was washed with brine and dried over magnesium sulfate. The solution was concentrated in vacuo and separated by silica gel column chromatography. Yield = 440 mg (30%).
1H-NMR (CDCI3) 67.38-7.17 (m, 5H, ClPh, thiazol) 6.81 (d,
J = 3.7 Hz, IH, thiazole), 4,02 (q, J = 7Hz, 2H, CH2NH),
3.17 (t, J = 7.1 Hz, CH2).
13C-NMR (CDCI3) δ 177.5 (C=S), 161 (thiazol), 137.5 (thiazol), 136.0 (ClPh), 134.1 (ClPh), 131.1 (ClPh), 129.5 (ClPh), 128.0 (ClPh) and 126.7 (ClPh) 111.1 (thiazol), 44.8
3C (CH2) and 32.3 (CH2).
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- 92 IL
Example 94 (2 - (2-methoxv) phenethyl )-N‘ -(2-thiazolyl) thiourea
Thereafter, EtOAc and The organic phase was
To a solution of 1.8 g (10 mmol) 1,1·thiocarbonyldiimidazole in CH2CI2 (30 ml) at 0°C was added 1.46 ml (10 mmol) of 2-methoxyphenethylamine. The solution was then stirred for 1 hour. After the addition of hexane, the reaction mixture was filtered and evaporated. The residue was dissolved in DMF (8 ml) and 1.0 g (10 mmol, 2aminothiazole (Merck) was added. The reaction mixture was heated at 100eC for about 16 h.
diluted HCl-solution were added, separated and washed with diluted HCl-solution, sat. NH4CIsolution and water (x 2), respectively. After drying over Na2SO4, the product was purified on a silica gel column, using hexanes/EtOAc (2:1) as eluent, to give 0.77 g crude product. Recrystallization from toluene gave 0.54 g of still crude titled product. A final purification was achieved by the use of a AI2O3 column eluted with CHCI3 (containing 0.5% EtOH) as the eluent. This gave 85 mg of the titled product.
Mp: 126.0-127.5°C.
1H-NMP. (CDCI3) δ 3.03 (t, 2H), 3.82 (s, 3H) , 3.96 (q, 2H), 6.79-6.93 (m, 3H), 7.20-7.26 (m, 3H,, 10.35 (broads, IH,, 10.73 (broad s, IH).
13C-NMR (CDCI3) δ 29.59, 45.69, 55.19, 110.22, 110.97,
120.40, 126.75, 127.96, 130.78, 137.72, 157.62, 161.58, 177.34.
Example 95
N- (2- (4-fluorplDheDethvll -Ν’ - (2-thiazolvl) thiourea In a manner analogous to Example 94, using 4fluorophenethylamine, the titled product resulted.
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- 93 Analyses: Calculated: C 51.22, H 4.30, N 14.93. Found: C 51.0, H 4.35, N 14.8.
Mp: 124.5-126.0°C.
iH-NMR (CDCl3) 8 3.0 (t, 3H), 4.0 (q, 3H) , 6.86 (d, IH,, 7.0-7.3 (m, 5H).
13C-NMR (CDCI3) 8 34.05, 46.82, 111.35, 115.38 (d, 20,
130.39 (d, 20, 134.20 (d, 1C), 137.46, 161.74 (d, 1C), 161.83, 177.52.
Example 36
N-(2-(4-nitro)Phenethvl)-Ν' -(2-thiazolvl)thiourea
In a manner analogous to Example 93, using 4nitrophenethylamine, the titled product resulted.
1H-NMR (CDCI3) δ 8.17 (d, J = 8.6 Hz, 2H, O2NPh), 7.45 (d,
J = 8.6 Hz, 2H, O2NPh), 7.21 (d, J = 3.7 Hz, IH, thiazole),
6.84 id, J = 3.7 Hz. IH, thiazole), 4.01 (q, J = 5.7 Hz,
2H, CH2NH), 3.15 (t, J = 7.2 Hz, 2H, CH2, .
13C-NMR {CDCI3 + CD3OD) δ 179 (C=S), 161 (thiazole), 146.4 (O2NPh), 136.9 (thiazole), 129 (O2NPh), 123.4 (02NPh),
111.1 (thiazole), 45.3 (CH2), 34.3 (CH2).
Example 97
Ν- (2- (4-amino)/phenethyl) -N'-(2-thiazolv 1) thiourea
The titled product was prepared by reduction of the product from Example 96 with iron and hydrochloric acid using the literature procedure (Vogel, Textbook of Practical Organic Chemistry. 4th ed., p.657, Longman 1978). 1h-NMR {CDCI3, 8 7.23 (d. J = 3.8 Hz, IH, thiazole), 7.07 id, J = 8.3 Hz, 2H, H2NPh,, 6.79 (d, J = 3.7 Hz, 1Η, thiazole), 6.65 (d, J = 8.3 Hz, 2H. H2NPh), 3.91 (q, 2H,
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- 94 13C-NMR (CDCI3 + CD3OD) δ 177 (C=S), 161 (thiazole), 144 (H2NPh), 137.3 (thiazole), 129.5 (H2NPh), 128.6 (H2NPh),
115.4 (H2NPh), 110.9 (thiazole). 46,7 (CH2), 33.6 (CH2).
Example 98
N- ¢2 - (4-methoxv) phenethvll -M'-(2-thiazolvl)thiourea
In a manner analogous to Example 93, using 4methoxyphenethy lamine, the titled product resulted.
Ικ-NMR (CDCI3) δ 7.22-7.18 (t, 3H, MeOPh and thiazole),
6.85 (d, J = 8.5 Hz, 2 H, MeOPh), 6.81 (d, J = 3.7 Hz, 1 H, thiazole), 3.94 (q, J = 7.1 Hz, 2 H, CH2NH), 3.79 (s, 3H, MeO), 2.96 (t, J = 7.1 Hz, 2H, CH2).
13C-NMR (CDCI3) δ 177.3 (C=s), 161.6 (thiazole) 158.2 (MeOPh), 137.4 (thiazole), 130.4 (MeOPh), 129.7 (MeOPh),
113.8 (MeOPh), 111.0 (thiazole), 55.1 (MeO), 47.0 (CH2),
33.8 (CH2).
Example 99
N- (2- (4-hydroxy) phenethyl) -N* - (2-thiazolvl) thiourea
The titled product was prepared by treatment of the product of Example 98 with iodotrimethyl silane in dichloroethane according to literature procedure (H.
Sakurai, Synthesis, p. 740, 1979) (Example 97).
iH-NMR (CDCI3) δ 7.22 (d, J = 3.6 Hz, IH, thiazole), 7.14 (d, J = 8.4 Hz, 2H, HOPh), 6.81-6.77 (t, 2H, thiazole,
HOPh), 3.94 (q, 2H, CH2NH2), 2.94 (t, J = 7.2 Hz, 2H, CH2). 13C-NMR (CDCI3) δ 177.4 (C=S), 161.4 (thiazole), 154.1 (HOPh), 137.6 (thiazole), 130.5 (HOPh), 129.9 (HOPh), 115.3 (HCPh), 110.9 (thiazole), 47.1 (CH2), 33.7 (CH2).
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- 95 Example 100
N- (2-14-bromo) phene thyll.-M,1.- (2-thiazolyl)thiaurea
In a manner analogous to Example 93, using 4bromophenethylamine, the titled product resulted. ih-NMR (CDC13 + CD3OD) δ 7.43 (d, J = 6.4 Hz, 2 H, BrPh),
7.22 (d, J = 3.6 Hz, 1 H, thiazole), 7.15 (d, J = 6.3 Hz, 2 H, BrPh), 6.83 (d, J = 3.7 Hz, 1 H, thiazole), 3.95 (t, J =
7.1 Hz, 2H, CH2NH), 2.94 (t, J = 7 Hz, 2H, CH2).
13C-NMR (CDCI3 + CD3OD) δ 177.5 (C=S), 161.5 (thiazole),
137.4 (thiazole), 131.5 (BrPh), 130.5 (BrPh), 120.3 (BrPh),
111.1 (thiazole), 46.2 (CH2), 34.0 (0¾).
Example 1Q1
MxUrJlzBipfiridinyl)ethvlJ -Ν' - (2-thiazolyl.) thiourea
In a manner analogous to Example 93, using 1piperidinylethylamine, the titled product resulted.
1H-NMR (CDCI3) δ 7.32 (d, J = 3.7 Hz, 1 H, thiazole), 6.84 (d, J = 3.7 Hz, IH, thiazole), 3.80 (t, 2H, CH2NH), 2.62 (t, J = 6.4 Hz, 2H, CH2), 2.48 (m, 2H, pip), 1.62 (m, 2H, pip), 1.46 (in, IH, pip).
13C-NMR (CDCI3 +CD3OD): 177.3 (C=S), 161 (thiazole), 137.3 (thiazole), 111.1 (thiazole), 56.1 (0¾), 54.1 (pip), 42.2 (0¾), 25.6 (pip), 24.0 (pip).
Example 102
N- (2-mQrpholinoethvl)-Ν' - (2-thiazolvl) thiourea
In a manner analogous to Example 91, using morpholinoethylamine, the title product resulted.
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- 96 1H-NMR (250 MHz, CDCI3) δ 7.38 (d, IH, CH=CH), 6.86 (d, IH, CH=CH), 3.82 (q, 2H, CH2-NH), 3.86-3.71 (m, 4H, CH2O-CH2). 2.67 (t. 2H,CH2-N (ring)), 2.62-2.52 (m, 4H, CH2-N-CH2).
13C-NMR (250 MHz, CDCI3) δ 178, 163, 138, 112, 67, 57, 53, 42.
Mp: 150.5 - 151.5°C.
Example 103
1-(2-Aminothiazole)-11-imidazole thiocarbonvl
8.90 g Thiocarbonyldiimidazole (50 mmole) and 5.0 g 2-aminothiazole (50 mmole) was added to 50 ml acetonitrile. The mixture was heated to 40eC, and stirred for 2 hours at this temperature. The mixture was cooled to 0°C, and the solid was filtrated off, and washed with 300 ml cold acetonitrile. The yield of pure product after drying was 9.7 g (46 mmole).
Elemental anal: Found; C=39.3, H=2.8, ih=26.2; Calc: C=40.0, H=2.87, N=26.6.
1H-NMR (250 MHz, DMSO) δ 8.68 (s, IH, N=CH-N), 7.97 (s, IH, N-CH=CH-N), 7.76 (d, IH, S-CH=CH-N), 7.33 (d, IH, S-CH=CHN), 7.08 (S, IH, N-CH=CH-N).
AP/P/ 95/00723
Example 1P4
Nr(2-Phenethvl)-N1 -f2-(6-hvdroxv)pvridvllthiourea
A stirred solution of phenethyl isothiocyanate (1.63 g, 10 mmol, 1.5 mL) and 2-amino-6-hydroxypyridine (1.10 g, 10 mmol) in N-methylpyrrolidinone (20 mL) was heated to 100®C. After 87.25 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic
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- 97 phase was washed with water (4x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (10% ethyl acetate/dichloromethane to 15% ethyl acetate), followed by trituration with ethyl acetate to provide 1.15 g of the titled product (42%) as an off-white solid:
mp 196-197eC;
IR (KBr, cm'1) 2937, 1668, 1595, 1475, 1428, 1365, 1219,
1158, 1023;
*H NMR (300 MHZ, DMSO-dJ δ 11.49 (br S, IH) , 10.82 (s, 1Η) , 10.33 (s, IH), 7.52 (t, J=7,9 Hz, IH), 7.25-7.14 (m, 5H),
6.53 (d, J=7.9 Hz. IH). 6.19 (d, J=8.0 Hz, IH), 3.80-3.73 (rn, 2H), 2.92 (t, J=7.7 Hz, 2H) ;
MS (FD) rn/e 273 (M+);
UV (EtOH) 305nm (€= 20692), 262nm (€=13737), 247nm (e=
18743), 203nm (€=19201).
Anal. Calcd for C14H15N3OS: C, 61.52; H, 5.53; N, 15.37. Found: C, 61.73; H, 5.72; N, 15.57.
Example 105
N- ¢2- (2-naphthyl) ethvl) -Ν’ - (2-thiazglvl) thiourea
2-Naphthalenethylamine (256 mg, 1.5 mmole) and the product from Example 103 (400 mg, 1.9 mmole) was suspended in IMF (5 ml). The reaction mixture was heated to 110eC and it became a clear solution in a few minutes. After 1 hour, the reaction mixture was cooled to room temperature, and 20 ml methylene chloride was added. The organic solution was washed successively with 0.5 N HCl solution (70 ml), brine (50 ml) and water (50 ml). The organic solution was dried over magnesium sulfate, and then
AP/P/ 9 5 / 0 0 7 2 3 bad original.
APO Ο Ο 388
- 98 cried in vacuo. The product was purified by silica gel column chromatography (chloroform/cyclohexane = 1/1 v/v) .
Yield = 324 mg (69%).
(CDCI3) δ 7.82-7.39 (m, 7H, naph), 6.98 (d, J = 3.6
Hz, 1H, thiazol), 6.73 (d, J = 3.1 Hz, 1H, thiazol), 4.07 (q, J = 7 Hz, 2H, CH2NH), 3.28 (t, J = 7 Hz, 2H, CH2) .
13C-NMR (CDCI3+CD3OD) δ 177 (C=S), 161 (thiazol), 137 (thiazol), 134.5 (naph), 133.6 (naph), 131.7 (naph), 128.5 (naph), 127.2 (naph), 126.8 (naph), 125.9 (naph), 125.5 (naph), 125.2 (naph), 123.6 (naph), 110.9 (thiazol), 45.8 (CH2), 31.7 (CH) . κ-,
OExample IQ6
N- (LrJ4-pent.enyll-N ' r 12.-.thiazolyl) thiourea 15 A mixture of 4-pentenol (3.04 g, 35.3 mmole), pyridine (2.79 g, 35.3 mmole) and 25 ml diethyl ether was cooled to -60°C. Trifluoromethanesulfonic anhydride (10 g,
35.4 mmol) was added dropwise at -60*C (5 min). The reaction was heated slowly (30 min) to room temperature, * and the salt formed was filtered off.
The filtrate was added dropwise to a mixture of 10 ml diethyl ether and 30 ml liquid ammonia kept at ca -30eC. The ammonia was evaporated while the remaining solution was allowed to reach room temperature. The ether solution was extracted with 10 ml 10 M aqueous sodium hydroxide. Distillation at atmosphere pressure gave 4pentenylamine (2.35 g, 27.6 mmole).
0.85 g (10 mmole) of this amine was condensed with 2.1 g of the product of Example 103 using the method >C as described in Example 105. Crystallization from a mixture of n-hexane and toluene gave pure product.
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- 99 1h-nmr (CDCI3) δ 1.85 ppm (m,, 2.20 ppm (m>, 3.7 ppm (m,,
5.0-5.15 ppm (m), 5.75-5.95 ppm (m,, 6.85 ppm Id), 7.30 ppm (d) .
13C-NMR (CDCI3, δ 177, 162, 137, 137, 116, 111, 45, 31, 28 5 ppm.
Example 1Q7
N- (2-(3-trifluoromethyl)phenethvl) -Ν' - (2-thiazolvl)thiourea
In a manner analogous to Example 106, using 110 trif luoromethyl-3-ethanolbenzene, the titled product resulted.
!h-NMR (CDCI3) δ 3.0 (t, PhCH2, 2H,, 4.0 (q, CH2N, 2H) , 6.8 (d, thiazole, IH), 7.2 (d, thiazole, IH,, 7.4-7.6 (mult, o, m and p, 4H).
Example lOfl
N- (ci s - 3 -Hexenvl)) _-N * - (2 - thiazolyl) thiourea
In a manner analogous to Example 106, using 3cis-hexenol, the titled product resulted.
3H-nmr (CDCI3) δ 7.30 (d, J = 3.9 Hz, 1 H, thiazol), 6.83 (d, J = 3.8 Hz, IH, thiazole), 5.56 and 5.40 (m, 2H, H-C=CH), 3.75 (q, 2H, CH2NH), 2.47 (q, 2H, CH2), 2.09 (p, 2H,
CH2), 0.95 (t, J = 5.4 Hz, 3H, CH3).
13C-NMR (CDCI3) δ 177 (C=S), 161 (thiazole), 137.5 (thiazole), 134.8 (C=C), 124.6 (C=C), 111.0 (thiazole),
45.4 (CH2NH), 26.3 (CH2), 20.6 (CH2), 14.1 (CH3).
AP/P/ 9 5 / 0 0 7 2 3
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- 100 Example 1Q9
N-(2-(1-nachthvl)ethvl)-Ν' -(2-thiazolvl)thiourea
In a manner analogous to Example 106, using (1napnthyl)-2-ethanol, the titled product resulted.
1H-NMR (CDCI3 + CD3OD) δ 8.24-7.40 (m, 7H, naph,, 7.16 (d,
J = 3.7 Hz, IH, thiazole), 6.80 (d, J = 3.7 Hz, IH, thiazole), 4.10 (t, J = 7.5 Hz, 2H, CH2NH), 3.49 (t, J =
7.5 Hz, 2H, CH2,·
Example 110
N-(2-(2-fluoro)-phenethy11-N‘-(2-thiazolvl)thiourea
In a manner analogous to Example 106, using 1fluoro-2-ethanolbenzene, the titled product resulted. XH-NMR (CDCI3) 57.28-7.03 (m, 5H, thiazole, FPh), 6.81 <d,
J = 3.8 Hz, IH, thiazole), 3.99 (q, J = 7.1 Hz, 2H, CH2NH),
3.08 (t, J = 7 Hz, 2H, CH2).
13C-NMR (CDCI3) δ 178 (C=S), 161 (thiazole), 137.4 (thiazole), 131 (d, C-F coupling, FPh), 128 (d, C-F coupling, FPh), 124 (FPh), 115.4 (FPh,, 115 (FPh), 111 (thiazole), 45.3 (CH2), 28.1 (CH2).
Example 111
N-(2-(2-trifluoromethvllphenethyl)-Ν' -(2-thiazolvl)thiourea
In a manner analogous for Example 106, using 125 trifluoromethyl-2-ethanolbenzene, the title product resulted.
^-H-NMR (CDCI3) δ 7.66 (d, IH, TFMPh), 7.51 (m, 2H, TFMPh, ,
7.34 (m, IH, TFMPh), 7.26 (d, J = 3.6 Hz, IH, thiazole),
6.84 (d. J = 3.8 Hz. IH, thiazole), 3.99 (q, J = 6.3 Hz, ?0 2H, CH2NH), 3.23 (t, J = 7.6 Hz, 2H, CH2).
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-10113C-NMR (CDCl3) δ 177.7 (C=S), 161.5 (thiazole), 137.6 (thiazole), 136.9 (TFMPh), 131.8 (TFMPh), 131.6 (TFMPh), 129 (q, C-F coupling, CF3), 126.6 (TFMPh), 125.9 (d, TFMPh), 111.1 (thiazole), 46.3 (CH2), 31.4 (CH2).
Example 112
N-N-(3-pentvnvl) -Ν' -(2-thiazolvl)thiourea
The starting material, 3-pentynylamine, was synthesized from 3-pentyn-l-ol.
2---Een£Ynvlamiag
Trifluoromethanesulfonic anhydride (4.0 ml; 23.8 mmol) was added to a solution of 3-pentyn-l-ol (2.0 g; 23.8 mmol) and pyridine (1.92 ml; 23.8 mmol) in diethyl ether (50 ml) at -45°C. The mixture was stirred for 15 min at the same temperature and filtered cold into diethyl ether (-10 ml) saturated with NH3 at -45°C with stirring. The precipitate was washed with cold diethyl ether. The reaction mixture was stirred at RT for 3 h and evaporated to give yellow crystals (2.0 g, 36 %) as a salt of 3pentynylamine and tri fluoromethane sulfonic acid.
iH-NMR (250 MHZ, D2O) 6 3.12 (t, 2H, CH2-NH+3), 2.55 (m,
2H, CH2-C=C), 178 (t, 3H,CH3-OC) .
13C-NMR (250 MHz, D2O) 6 126, 83, 77, 41, 20, 5.
The titled product was then prepared in a manner analogous to Example 106.
iH-NMR (250 MHz, CDCl3) δ7.33 (d, IH, CH=CH) , 6.87 (d, IH, CH=CH) , 3.86 (q, 2H, CH2-NH), 2.56 (tt, 2H, CH2-CaC,, 1.81 (t, 3H,CH3-CSC).
13C-NMR (250 MHz, CDCI3) δΐ78, 162, 138, 111, 45, 19. 4.
Mp: 118.5-119.5®C.
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-102Example 113
3- ί2-Phenethyl)-2-thioxo-1,2.3.4-tetrahvdroauinazoline
2-Nitrobenzaldehyde (10.0 g, 66 mmol) and 2phenylethylamine (8.3 ml, 66 mmol) was dissolved in acetonitrile (200 ml). pH was adjusted to 6.0 with acetic acid.
Sodium cyanoborohydride (4.15 g, 66 mol) was added in small portions. The solution was stirred 40 min. The solution was diluted with water (400 ml) and extracted with ether.
Acid-base partitioning (aq. HCl, NH4OH (aq.,] and evaporation gave an oil. The oil was suspended in water (200 ml) and iron dust (10 g, 180 mmol) was added. The mixture was heated to reflux and HCl (cone, aq.) (10 ml) was slowly added. Reflux was continued for 40 minutes. The solution was cooled, basified with sodium hydroxide 40 % (aq.) to pH 14. The solution was stirred with toluene (700 ml) and filtered through a pad of celite.
Acid-base partitioning ((HCl (a.q.) NH4OH (a.q.)] and evaporation afforded an oil. The oil was dissolved in acetonitrile (20 ml, and N,N-thiocarbonyldiimidazole (0.7 g, 6.6 mmol) was added. The solution was stirred for 78 hours at ambient tenqperature, heated to 75°C for 40 minutes and evaporated. The residue was purified by flash-chromatography on silica gel by elution with ethyl acetate-cyclohexane (1:3). The product crystallized spontaneously from the pure fractions forming long needles. 1H-NMR (CDCI3) δ 3.0 (t, PhCH2, 2H) , 4.1 (t, PhCH2£H2N'
2H) , 4.4 (s, PhCH2N, 2H) , 6.7-7.5 (mult., C5H5, C5H4, 9H),
AP/P/ 95/00723
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- 103 Example 114
N- (2-Phenethyl).-2L'.r £2-.,(3 -methyl.).?pyridy 11. thiourea
A stirred solution of 2-phenethyl isothiocyanate (1.63 g, 10 mmol, 1.5 mL) and 2-ami no-3-me thy lpyridine
Ί.08 g, 10 mmol) in N-methylpyrrolidinone (20 mL) was heated to 100°C. After 16.5 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with water (4x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (2% ethyl acetate/dichloromethane, to provide 1.77 g of the titled product (65%). This material was recrystallized from ethyl acetate/hexanes to provide 878 mg of the titled product as a pale yellow crystalline solid:
mp 82-84°C; IR (KBr, cm'1) 3430, 2945, 1594, 1555, 1454, 1268, 1243, 1161;
NMR (300 MHZ, DMSO-d6) 811.62 (br s, IH,, 8.66 (s, IH),
7.90 (d, J=4.1 Hz, IH,, 7.59 (d, J=7.2 Hz, IH), 7.28-7.15 (m, 5H), 6.96 (dd, J=7.4, 5.0 Hz, IH), 3.84-3.78 (m, 2H,,
2.89 (t, J=7.0 Hz, 2H), 2.23 (s, 3H);
MS (FD) m/e 271 (M+,; UV (EtOH) 293nm (¢=17290), 265nm (e= 14634), 244nm (¢=16338), 202nm (¢=19784).
Anal. Calcd for C15H17N3S: C, 66.39; H, 6.31; N, 15.48.
Found: C, 66.66; H, 6.32; N, 15.73.
Example 115
N~i2- (2-thienyl.) ethvl) -N* - (2-thiazolyl) thiourea
6.4 g 2-(2-thienyl)ethanol (50 mmoles) was dissolved in 50 ml diethyl ether together with 3.95 g pyridine (50 mmoles)._
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- 104 10
The mixture was cooled to -30eC, and 5.7 g methanesulfonylchloride (50 mmoles, was added dropwise under stirring. The reaction mixture was then heated and kept at reflux temperature for 30 minutes. The mixture was then cooled to room temperature and filtered. The filtrate was transferred to an autoclave together with 100 ml of a solution of ammonia in methanol (saturated at 0°C) . The autoclave was sealed and heated to 150°C for 17 hours. The solvent, was removed by evaporation in vacuo, and 100 ml 5 M sodium hydroxide in water was added. The mixture was extracted twice with 100 ml methylene chloride to give a solution of 2-(2-thienyl)ethylamine together with some secondary amine.
The pure primary amine was obtained by fractional crystallization from methanol of the salts with oxalic acid, followed by addition of aqueous sodium hydroxide and extraction with methylene chloride.
500 mg of the pure 2-(2-thienyl)ethylamine (3.93 mmole) was added to a solution of 800 mg thiocarbonyldiimidazole (4.5 mmole) in 5 ml methylene chloride at 0°C. The mixture was stirred at 0eC for 15 minutes, and then 1 hour at 20°C. The solvent was removed in vacuo, and 5 ml dimethylformamide and 500 mg 2-aminothiazole was added.
This mixture was allowed to react 17 hours at 110°C. After evaporation of solvent in vacuo 100 ml ethyl acetate was added, and the mixture was heated to 50°C. The warm mixture was washed twice with 20 ml 1 M HCl, and once with 20 ml H2O. Evaporation of solvent to a small volume gave crystals of the desired product. Recrystallization twice from ethyl acetate gave 340 mg of very pure product.
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-10513C-NMR (CDCI3 + DMSO-d6) δ 178, 162, 141, 137, 127, 125, 124, 111, 46, 29 PPM.
^-H-NMR (CDCI3 + DMSO-de) 6 3.3 ppm (t), 3.9 ppm (m,, 6.85 ppm (d), 6.90 ppm (m), 7.20 ppm (d), 7.25 ppm (d).
Example 116
M.-12-.12-£luoro-6-chloro} pheaethvl) -Ν' - (2-thiazolyl}thiourea
2-Chloro-6-fluorophenylacetonitrile (2.5 g, 14.7 mmol) was dissolved in 30 ml diethyl ether. Lithium aluminium hydride (1.5 g, was added in small portions over a period of 10 minutes. The mixture was then heated to reflux for 15 minutes. After cooling to room temperature,
1.5 ml water, 1.5 ml aqueous sodium hydroxide, and 4 ml water was added slowly. The ether solution containing the product 2-chloro-6-fluorophenethylamine was decanted off and the solvent was removed in vacuo.
The amine formed was condensed with the product of Example 103 using the method as described in Examples 104 and 105 to give 270 mg of the titled product after recrystallization from ethanol.
iH-NMR (DMSO-d6) δ 3.1 ppm (t), 3.85 ppm (m,, 7.1 ppm (d),
7.15-7.30 ppm (m), 7.40 ppm (d).
Example 117
K=12x.U.-Methoxyi -.Phenethyl) -Ν' - (2-thiazolvl) thiourea
In a manner analogous to Example 105, the product of Example 103 was condensed with 3AP/P/ 9 5 / 0 0 7 2 3
AP000388
-1061H-NMR (DMSO-dg) δ 2.9 (t, Ph, CH2, 2H), 3.75 (s, OCH3,
3H), 3,9 (q, CH2N, 2H), 6.8 (mult. 0 and p, 4H), 7.1 (d, thiazole, IH), 7.2 (t, m, IH), 7.4 (d, thiazole, IH).
Example 118
N-(2-Phenethv 11-Ν’ -_L2- (5-methvl)pvridvl 1 thiourea
A stirred solution of 2-phenethyl isothiocyanate (1.63 g, 10 mmol, 1.5 mL) and 2-amino-5-methylpyridine (1.08 g, 10 mmol) in N-methylpyrrolidinone (20 mL) was heated to 125*C. After 16.5 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with water (4x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (2% ethyl acetate/dichloromethane) to provide 2.01 g of the titled product (74%). This material was recrystallized from ethyl acetate/hexanes to provide 1.72 g of titled product as a white crystalline solid:
mp 153-154eC; IR (KBr,cm1) 3235, 2939, 1613, 1559, 1534, 1493, 1300, 1188;
XH NMR (300 MHZ, DMSO-d6) δ 11.56 (br S, IH) , 10.42 (s, IH) ,
AP/P/ 9 5 / 0 0 7 2 3
7.84 (d, J=1.3 Hz, IH), 7.52 (dd, , J=8.5, 2.1 Hz, IH), 7.31
7.16 (m, 5H), 6.99 (d, J=8.5 Hz, IH), 3.82-3 .75 (m, 2H),
25 2.87 (t, J=7.0 Hz, 2H), 2.16 (s, 3H);
MS (FD) ra/e 271 (M+);
UV (EtOH) 298nm (€=14080), 268nm (€=21638), 248nm (e= 15905), 201nm (€=18504).
Anal. Calcd for C15H17N3S: C, 66.39; H, 6.31; N, 15.48. 30 Found: C, 66.33; H, 6.26; N, 15.33.
BAD ORIGINAL ffl
AP 0 0 0 3 8 8
-107Examole 119
N-Methyl -N- L2 -phenethyl),.-N- I2.r thiazolvl 1 thiourea
In a manner analogous to Example 105, the product of Example 103 was condensed with N-methylphenethyIamine, to give the titled product. iH-NMR (DMSO-dg) δ2.9 (t, PhCH2,2H) , 3.2 (s,NCH3,3H) 4.0 (t, CH2N,2H), 6.8 (d,thiazole,IH), 7.2(m, thiazole,IH), 7.3(mult.,CgH5,5H)
Example 12Q
N-(2-Indanvl)-N'-(2'-thiazolvl) thiourea
In a manner analogous to Example 105, the product of Example 103 was condensed with 2indanyIamine, to give the titled product. i-H-NMR (DMSO-d6) δ2.4 (q, CH2» 2H), 3.3 (q, CH2, 2H),
4.8 (q, CHN, IH) , 7.0 (d, thiazole, IH), 7.1-7.3 (mult., CgH4, 4H), 7.4 (d, thiazole, IH).
Example 121
N-.(2- (2.-hZLida.) -phenethyl) -M‘ - (2-thiazolyl) thiourea
2-Aminophenethylalcohol (Aldrich) (0.8 g, 5.8 mmol) was dissolved in 15 ml H2O at O’C. Trifluoroacetic acid (1.2 ml) was added. Sodium nitrite (0.41 g, 0.6 mmol) dissolved in cold water (2.0 ml) was added. The solution was stirred at O’C for 10 minutes.
Lithium azide (0.59 g, 12 mmol) in water (2.0 ml, was added slowly. The solution was brought up to ambient temperature. The solution was extracted with diethyl ether (3 x 50 ml), the organic phase was washed with 1 N HCI (aq.) (2 x 20 ml), dried with Na2SO4,
AP/P/ 9 5 / 0 0 7 2 3
ΑΡΜΟ 3 88
-108The residue was dissolved in dichloromethane (20 ml) under a nitrogen atmosphere. The solution was cooled to -10°C and ethyldiisopropylamine (1.1 ml, 6.4 mmol) was added.
Trifluoromethanesulfonic anhydride (0.87 ml,
5.17 mmol) was added dropwise. The solution was stirred at 0° for 20 minutes and then added to a solution of NH3 (g) in methanol (50 ml sat. at 0°C, under vigouros stirring. The solution was stirred for 40 minutes at ambient temperature. The solution was diluted with water (100 ml) and extracted with dichloromethane (2 x 50 ml). Acid-base partitioning [NH4OH (aq)-HCl (aq)( and evaporation gave 2-azidophenethylamine.
In a manner analogous to Examples 104 and
105, the product of Example 103 was condensed with 2azidophenethylamine, to give the titled product.
I-H-NMR (DMSO-d6) δ 2.9 (t, PhCH2, 2H) , 3.8 (q, CH2N,
2H), 7.0-7.4 (m, Ph-o, m, p, thiazole, 6H,.
Example 122
N.- (2 - ί3-Fluoro)Phenethyl) -N* - (2-thiazolvl) thiourea
In a manner analogous to Example 105, the product of Example 103 was condensed with 3fluorophenethylamine to give the titled product.
3H-NMR (DMSO-d6, δ 2.9 (t, PhCH2, 2H), 3.8 (q, CH2N,
2H) , 7.0-7.4 (m, Ph-o,m,p, thiazole, 6H).
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-109Example 123
N- (2- (BenzenesulfQnamid&--4-ethvUl-N'-12_thiazolyl) thiourea
In a manner analogous to Example 105, the 5 product of Example 103 was condensed with 4-(2amincethyl )benzenesulfonamide to give the titled product.
^H-NMR(DMSO-d6) 8 3.0(t), 3.8(m), 7.1(d), 7.35(m), 7.45(d). 7.80(d).
13C-NMR (CMSO-d6) δ 178, 162, 143. 142, 137, 129, 126,
112, 45, 34.
Example 124
N- (2 -.(3,4-Dimethoxv)phenethvlL-M1 - (2-thiazolvl 1 thiourea 15 In a manner analogous to Example 105, the product of Example 103 was condensed with 3,4dimethoxyphenethylamine to give the titled product. !h-NMR (DMSO-d6-CDCl3) δ 2.95 (t), 3.70 (t), 3,85 (s),
3.90 (s), 6.80 (s), 6.90 (d), 7.40 (d).
Example 125
N- (PhenvlDroDan-l-ol-2-vl)-Ν' - (2-thiazolvl) thiourea
In a manner analogous to Example 105, the product of Example 103 was condensed with norephedrine to give the titled product.
iH-NMR (DMSO-d6) δ 0.95 (d) , 4.25 (m), 4.95 (d), 7.1-7.5
AP/P/ 9 5 / 0 0 7 2 3
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-110Ν- (2- (2-Pvridvl)ethvl)-Ν' - (2-thiazolyl) thiourea
In a manner analogous to Example 105, the product of Example 103 was condensed with 2-(25 aminoethyl)pyridine to give the titled product.
1H-NMR (DMSO-dg) δ 3.1 (t,, 4.0 (m) , 7.1 (d,, 7.2-7.4 (m). 7.7 (m), 8.5 (d), 9.8 (s), 11.7 (s).
Example 127
N-(2- (2,5-Dimethoxy)phenethyl)-N'- (2-thiazolvl) thiourea
In a manner analogous to Example 105, the product of Example 103 was condensed with 2,6dimethoxyphenethylamine to give the titled product. iH-NMR (CDCI3) δ 3.00 (t), 3.73 (s), 3.77 (s), 3.97 (m) ,
6.70-6.85 (m), 7.24 (d), 10.80 (s).
13C-NMR (CDC13) δ 177, 162, 153, 152, 138, 128, 117,
112, 111, 111, 56, 56, 46. 30.
Example 128
N- (1- (2-Phenvl)propanvl) -N* - (2-thiazolvl) thiourea
In a manner analogous to Example 105, the product of Example 103 was condensed with l-amino-2phenylpropane to give the titled product.
iH-NMR (DMSO-d6) δ 1.20 (d), 3.13 (q), 3.70 (t), 7.09 (d,, 7.20-7.50 (m).
Broad peaks δ 8.14, 9.33, 9.75 and 10.57.
AP/P/ 9 5 / 0 0 7 2 3
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-111Example. 129
N - i 2 -13 -. Indol) ethyU -N1 - .12 - thiazolyl Lthiourea in a manner analogous to Example 105, the product of Example 103 was condensed with tryptamine to give the titled product.
iH-NMR (CDCI3 ♦ CD3OD) δ 7.68-7.06 (m, 6H, indole, thiazole), 6.84 (d, J = 3.7 Hz, IH, thiazole), 4.02 (t,
J = 7 Hz, 2K, CH2NH,, 3.16 (t, J = 6.9 Hz, 2H, CH2). 13C-NMR (CDCI3 + CD3OD) 6 177 (thiazole), 161 (thiazole), 137 (thiazole), 136 (indole), 127 (indole), 123 (indole), 121 (indole), 118 (indole), 117 (indole), 111 (thiazole), 110 (indole), 109 (indole), 46 (CH2), 26 (CH2).
Example 130
N.~.(27 (2-hydroxyethoxv) ethvl) -Ν' - (2-thiazolvl) thiourea
In a manner analogous to Example 105, the product of Example 103 was condensed with 2-(2aminoethoxy) ethanol to give the titled product. iH-NMR (CDCI3) δ 7.34 (d, J = 3.4 Hz, IH, thiazole),
6.84 (d, J = 3.4 Hz, IH, thiazole), 3.96 (t, J = 4.9 Hz, 2H, CH2NH), 3.76 (m, 4H, CH2), 3.66 (t, J = 4.3 Hz, 2H, CH2) .
i3C-NMR (CDCI3) δ 177.4 (C=S), 161.8 (thiazole), 137.5 (thiazole), 111.2 (thiazole), 72.1, 68.4, 61.5, 44.9.
Example 131
Νζ-ί27 (5.-Nitropvrid-2-vl)aminoethvl) -Ν' - (2bhiazolvl) thiourea
In a manner analogous to Example 105, the product of Example 103 was condensed with 2-(2AP/P/ 9 5 / 0 0 7 2 3
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-112aminoethyiamino)-5-nitropyridine to give the titled product.
iH-NMR (CDCI3 + CD3OD) δ 8.95 (d, IH, pyr, , 8.12 (dd,
IH, pyr,, 7.26 (d, J = 3.8 Hz, IH, thiazole), 6.86 (d, J = 3.8 H2, IH, thiazole), 6.52 (d, IH, pyr), 3.99 (t, 2H,
CH2NH,, 3.78 (t, 2H, CH2).
Example 132
N-(2-(l-MethvlPvrrolid-2-vl)ethvl)-N1-(210 thiazolyl)thiourea
In a manner analogous to Example 105, the product of Example 103 was condensed with 2-(2aminoet'nyl)-1-methylpyrrolidine to give the titled product.
iH-NMR (CDCI3) δ 7.32 (d, J = 4 Hz, IH, thiazole), 6.83 (d, J = 3.6 Hz, IH, thiazole), 3.78 (q, 2H, CH2NH,, 3.08 (m, IH, NCH(CH2)2)’2 ·34 (s, 3H, N-CH3) , 2.16 (m, 2H, NCH2), 2.01 (m, 2H, CH2), 1.7 (m, 4H, pyr,.
13C-NMR (CDCI3, δ 177 (C=S,, 161 (thiazole), 137.5 (thiazole), 111.1 (thiazole), 64.1 (pyr), 57.1 (pyr),
43.1 (CH2), 40.6 (CH2), 32.1 (pyr,, 30.3 (pyr), 22.2 (pyr).
Example 133
N- 12.-12 /.4 -Pichiorp.)Phenethyl) -N* - (2-thiazolvl) thiourea
In a manner analogous to Example 105, the product of Example 103 was condensed with 2,4-dichloropherethylamine to give the titled product.
iH-NMR {CDC13 + CD3OD) δ 7.40 (d, IH, thiazole), 7.41
AP/P/ 9 5 / 0 0 7 2 3
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-113Example 134
N- (1.1 - (2 -p-hvdroxvphenvl)methoxvcarbcnvlethvl) -N' - ί 2thiazolyl thiourea
In a manner analogous to Example 105, the product of Example 103 was condensed with tyrosine methylester to give the titled product.
1H-NMR (CDCI3) δ 7.25 (d, J = 3.3 Hz, 1H, thiazole),
7.02 (d, J = 8.2 Hz, 2H, Tyr), 6.82 (d, J = 3.4 Hz, IH, thiazole), 6.74 (d, J = 8.2 Hz, 2H, Tyr), 5.29 (t, IH, CH), 3.73 (s, 3H, CH3), 3.19 (d, 2H, CH2).
13C-NMR (CDCI3) 8 177.4 <C=S), 171.5 (CO2Me), 161.2 (thiazole), 155.4 (Tyr), 136.9 (thiazole), 130.0 (Tyr),
126.2 (Tyr), 115.0 (Tyr), 111.1 (thiazole), 59.0 (CH) ,
51.9 (CH3), 36.4 (CH2).
Example 135
1- (2-Thiazolyl) -4- (p-hvdroxvbenzvl) -2-thiohvdantoin
The titled product was obtained as a by product during the preparation of the product described in Example 134.
l-H-NMR (CDCI3 + CD3oD) 8 7.78 (d, IH, thiazole), 7.50 (d. IH, thiazole), 7.07 (d, 2H, Tyr), 6.78 (d, 2H, Tyr),
4.50 (t, IH, CH), 3.15 (m, 2H, CH2).
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Example 136
N- (2-tranarPhenylcvclQDrQPvl) -Ν' -2- (thiazolyl) thiourea
In a manner analogous to Example 105 the product of Example 103 was condensed with trans-2phenylcyclopropylamine to give the titled product.
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-1141H-NMR (CDCI3 + CD3OD) δ 7.32 (d, J = 3.8 Hz, IH, thiazole), 7.23 (m, 5H, Ph), 3.38 (m, IH, CHNH), 2.27 (m, IH, CH), 1.91 {ra, 2H, CH2).
13C-NMR (CDCI3 + CD3OD) δ 179.2 (C=S), 161.7 (thiazole),
139.8 (Ph), 137.3 (thiazole), 128.2 (Ph), 126.5 (Ph), 126.0 (Ph), 111.2 (thiazole), 36.1 (CH), 35.1 (CH), 16.1 (CH2).
Example 137
N- (4-Methvl-3-pentenvl)-N’- (2-thiazolvl) thiourea
The starting material, 4-methyl-3-pentenylamine, was prepared from 5-bromo-2-methyl-2-pentene.
4^Hethyl-3-pentenYlamijQS
L1N3 (1 g, 20 mmol) was added to a solution of
5-bromo-2-methy 1-2-pentene (1.63 g, 10 mmol) in 5 ml DMF. The solution was stirred at room temperature for two days. The reaction mixture was poured into a mixture of hexanes and sat. NH4Cl-solution. The organic phase was washed with sat. N^Cl-solution, brine and water.
After drying, the solvent was removed and the crude azide was reacted with L1AIH4 (380 mg, 10 mmol) in ether at 0°C. After 2 h the reaction was quenched by the addition of 380 μΐ H2O, 380 pi 15 % NaOH-solution and 1.14 ml H2O, respectively. After filtration the solvent was evaporated and the residue was distilled in vacuo to give 0.42 g of the title amine.
B.p. 50°C/40 mm.
1H-NMR (CDCI3) δ 1.5 (broad s, 2H)., 1.60 (d, 3H), 1.70 (d, 3H), 2.68 (q, 2H), 5.05-5.15 (m, IH).
AP/P/ 9 5 / 0 0 7 2 3
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-11513c-nmr (CDC13) δ 17.70, 18.39, 25.66, 32.22, 42.03, 121.64, 133.50.
In a manner analogous to Example 105, the 5 product of Example 103 was condensed with 4-methyl-3pentenylamine to give the titled product.
Mp: 87.5-88.5°C.
Analyses: Calculated: C 49.76, H 6.26, N 17.41. Found: C 49.35, H 6.20, N 17.15.
^H-NMR {CDCI3) δ 1.65 (s, 3H), 1.75 (s, 3H), 2.40 (q,
2H), 3.73 (q, 2H), 5.1-5.25 (m, 1H), 6.83 (d, 1H), 7.29 (d, 1H) .
i^C-NMR (CDCI3) δ 17.93, 25.88, 27.31, 45.54, 111.22, 120.40, 135.10, 137.51, 161.94, 177.21.
Example.138
N- (.Trans-J chexenyll ?.N-‘ _(2-thiazplyll thiourea
The starting material, trans-3-hexenylamine. was prepared from trans-3-hexen-l-ol.
Irana-3 -hexenvlamine
To a stirred solution of trans-3-hexen-l-ol (5.0 g, 0.050 mol), Et2N (7.65 ml, 0.055 mol) and CH2CI2 (70 ml) at -30°C was added 4.33 ml (0.055 mol) methanesulfonyl chloride. The solution was stirred at about -20°C for 2 h. After addition of CH2Cl2, the organic phase was washed with sat. NaHCO3 solution, sat. NH4Cl-solution and water, dried (Na2SO4) and concentrated in vacuo. This gave a crude mesylate which was dissolved in DMF (30 ml) and Ι,λΝβ (5 g, 100 mmol)
AP/P/ 9 5 / 0 0 7 2 3
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-116was added. The reaction mixture was stirred overnight and poured into a mixture of ether and brine. The ether phase was washed with brine (x 2) and dried (Na2SO4).
The ether solution was concentrated to about 100 ml and 5 cooled to 0eC, whereafter 1.9 g (50 mmol) of LiAlH4 was added. After 1 h the reaction was quenched with 1.9 ml H2O, 1.9 ml 15 % NaOH-solution and 5.7 ml H2O, respectively. After filtration, the solvent was evaporated and the residue was distilled in vacuo to give 2.35 g of the titled amine.
B.p. 34°C/20 mm 3H-NMR (CDCI3) δ 0.92-1.05 (m, 3H), 1.75 (broad s, 2H),
1.95-2.20 (m, 4H), 2.68-2.75 (m, 2H), 5.27-5.63 (m, 2H). l^C-NMR (CDCI3) δ 13.80, 25.55, 36.62, 41.56, 126.10,
134.48.
In a manner analogous to Example 105, the product of Example 103 was condensed with trans-3hexenylamine to give the titled product.
Mp: 116.0-117.0°C.
Analyses: Calculated: C 49.76, H 6.26, N 17.41. Found: C
49.6, H 6.3, N 17.4.
1H-NMR (CDCI3) δ 0.98 (t, 3H,, 2.0-2.1 (m, 2H) , 2.41 (q, 2H), 3.76 (q, 2H), 5.4-5.7 (ra, 2H), 6.83 (d, IH), 7.29 (d, IH,, 10.8 (broad s, IH), 11.35 (broad s, IH).
i3C-NMR (CDCI3) 5 13.72, 25.65, 45.42, 111.25, 124.97, 135.56, 137.50, 161.95, 177.14.
AP/P/ 95/00723 ?0 *5AD ORIGINAL £
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-117Examcle 129
N-I2-(Cvclo-2-penten-l-vl)ethvll-N*-(2thiazolyl) thiourea
The starting material 2-(cyclo-2-penten-lyl)ethylamine was prepared from 2-cyclopenten-l-yl acetic acid.
2_- (Cvclo-2-penten-l-vl) ethylamine
2-Cyclopenten-l-ylacetic acid (5 ml, 0.042 mol) was dissolved in ether (100 ml,. LXAIH4 (2.4 g,
0.063 mol) was added in portions. After the addition, the reaction mixture was stirred for 2 h at room temperature. The reaction mixture was quenched with 2.4 g H2O, 2.4 g 15 % NaOH-solution and 7.2 ml H2O, respectively. Filtration and evaporation of the solvent gave 4.45 g of crude 2-(cyclo-2-penten-1-yl,ethanol.
This alcohol was transformed to the title amine by a procedure analogous to Example 138.
j-H-NMR (CDCI3) δ 1.4-1.8 (m, 4H,, 2.0-2.15 (m, IH) , 2.22.4 (m, 3H,, 2.6-2.8 (m, 3H), 5.6-5.8 (m, 2H).
13C-NMR (CDCI3) δ 29.68, 31.78, 40.00, 40.64, 42.97, 130.29, 134.61.
In a manner analogous to Example 105, the product of Example 103 was condensed with 2-(cyclo-2penten-l-yl)ethylamine to give the titled product.
Mp: 139.0-140.0°C.
Analyses: Calculated: C 52.14, H 5.97, N 16.58. Found: C 52.20, H 6.05, N 16.35.
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1H-NMR (CDCX3; 1 δ 1.42-1.58 (m, IH), 1. 62-1.92 (m, 2H) ,
2.06-2.45 (m, 3H), 2.72-2.86 (m, IH), 3.71-3.84 (m, 2H) ,
5.70-5.80 (m, 2H), 6.85 (d, IH), 7.32 (d, IH), 10.9
(broad s. IH), , 10.95 (broad s, IH).
13C-NMR (CDC13) δ 29.71, 32.01, 34.77, 43.23. 44.31, 111.15, 131.19, 134.13, 137.66, 161.99, 177.28.
Example 14Q
N-(2-(trans-3-pentenyl))-Ν' -(2-thiazolvl)thiourea
The starting material trans-3-penten-l-ol was prepared by reduction of 3-pentyn-l-ol with lithium aluminium hydride in refluxing tetrahydrofuran and the titled product was then prepared in a manner analogous to Examples 106 and 112.
iH-NMR (250 MHz, CDCI3) δ 7.28 (d, IH, CH=CH), 6.83 (d,
IH, CH=CH), 5.66-5.38 (m, 2H, trans-CH=CH), 3.67 (q, 2H, CH2-NH), 2.37 (q, 2H, CH2-CH=CH), 1.72 (dd, 3H, CH=CHCH3) .
13C-NMR (250 MHz, CDCI3) δ 177, 162, 138, 129, 127, 111, 46, 32, 18.
Mp: 129-129.5°C.
Anal. Calcd. for C9H13N3S2: C, 47.5; H, 5.7; N, 18.5. Found: C, 47.9; H, 5.8; N, 17.8.
Example, 141
N-(2-(cis-3-Pentenyl))-Ν' -(2-thiazolvl) thiourea
The starting material cis-3-penten-l-ol was prepared by reduction of 3-pentyn-l-ol with hydrogen in acetone at about 5 psi for 20 minutes using palladium on calcium carbonate as a catalyst (Lindlar catalyst), and
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-119the titled product was then prepared in a manner analogous to Examples 106 and 112.
1h-NMR (250 MHz, CDCI3) 67.30 (d, IH, CH=CH), 6.83 (d,
IK, CH=CH), 5.73-5.34 (m, 2H, cis-CH=CH), 3.76 (q, 2H,
CH2-NH), 2.48 (q, 2H, CH=CH-CH2, , 1.66 (d, 3H,CH=CHCH3) .
13C-NMR (250 MHz, CDCI3) δ 177, 162, 138, 127, 126, 111, 45, 26.
Mp: 76.5°C.
Example ,142
N- (2- (2-Methvl) -phenethyl)-N1 - (2 - thiazolvU-thiourea
The starting material 1-methylphenethanol was prepared by reduction of o-tolylacetic acid with lithium aluminium hydride in refluxing tetrahydrofuran and the titled product was then prepared analogous to Examples 106 and 112.
Mp: 143-144®C.
Example 143
IL- (2-(3,.
thiazolyl)thioure^
The starting material 2-(3,4,5-trimethoxy) phenethylamine was prepared by reduction of 3,4,525 trimethoxyphenylacetonitrile with cobalt chloride and sodium borohydride, according to the general method described by L.S. Heinzman in J. Am. Chem. Soc. Ifil, P6801 (1982).
3,4,5-Trimethoxybenzonitrile (965 mg, 5 mmole) and cobalt chloride (2,37 g, 10 mmole) were dissolved in methanol (70 ml). To the solution was added sodium
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-(20borohydride (1.89 g, 50 mmole). After 3 hours, the reaction mixture was filtered through celite, and concentrated to small volume. It was then taken up in chloroform and extracted with IN HCl (100 ml). The organic phase was discarded. The aqueous solution was basified with aqueous ammonia, and extracted with chloroform. The organic phase was dried over magnesium sulfate, and dried in vacuo to yield 2-(3,4,5trimethoxy)phenethylamine (427 mg).
1H-NMR (CDCI3) δ 6.58 (s, 2H, TMPh), 3.85 (m, 8H, 2 x MeO, CH2), 3.82 (s, 3H, OMe), 3.80 (m, 2H, CH2).
The titled product was then prepared analogous to Example 105.
iH-NMR (CDCI3) δ 7.26 (d, IH, thiazole), 6.85 (d, IH, thiazole), 6.64 (s, 2H, TMPh), 4.84 (d, J = 5.7 Hz, 2H, CH2NH), 3.86 (m, 11H, CH2, MeO).
13C-NMR (CDCI3) δ 177 (C=S), 161 (thiazole), 153 (TMPh),
138 (TMPh), 137 (thiazole), 132 (TMPh), 111 (thiazole),
104.8 (TMPh), 61 (MeO), 56.1 (MeO), 53 (CH2>, 50 (CH2).
Example 144
N-(2-(2.4-Difluoro)Phenethyl)-N·-(2-thiazolvl)thiourea
In a manner analogous to Example 143, using
2,4-difluorophenylacetonitrile, the titled product resulted.
!h-NMR (CDCI3) δ 7.26 (m, IH, DFPh), 7.20 (d, IH, thiazole), 6.80 (d, IH, thiazole), 6.75 (m, 2H, DFPh),
3.85 (q, 2H, CH2NH), 3.04 (t, 2H, CH2).
£ 2 L 0 0 I S 6 /d/dV
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-121Example 145
N- (2- (2.6-Diflucro)phenethyl)-Ν' -(2-thiazolvl) thiQurea
In a manner analogous to Example 143, using
2,6-difluorophenylacetonitrile, the titled product resulted.
^-H-NMR (CDCI3) δ 7.23 (d, J = 3.8 Hz, IH, thiazole),
7.26-7.12 (m, IH, DFPh), 6.86 (m, 2H, DFPh), 6.81 (d, J = 3.6 Hz, IH, thiazole), 3.96 (q, 2H, CH2NH,. 3.11 (t, J = 7 Hz, CK2).
13c-nmr (CDC13) δ 177 (C=S), 164 and 159 {dd, C-F coupling, DFPh), 162 (thiazole), 137 (thiazole), 128 (m, C-F coupling, DFPh), 111 (thiazole), 110.8 (d, C-F coupling, DFPh), 44.5 (CH2), 21.6 (CH2).
Example 146
N- (2.- L3^.irMethylenedioxY) phenethyl) tM,·,,-. (2.-.
thiazolyl) thiourea
In a manner analogous to Example 143, using
3,4-methylenedioxyphenylacetonitrile, the titled product resulted.
!h-NMR (CDCI3) δ 7.24 (d, IH, thiazole), 6.80 (m, 3H,
Ph, thiazole), 6.74 (s, IH, Ph), 5.93 (s, 2H, OCH2O), 3.94 (q, 2H, CH2NH), 2.93 (t, 2H, CH2).
13c-NMR (CDCI3) δ 177.3 (C=S), 161.6 (thiazole), 148 (Ph), 146 (Ph), 137.4 (thiazole), 132.1 (Ph), 111.1 (thiazole), 109.2 (Ph), 108.2 (Ph), 100.7 (0CH2O), 47.0 (CH2), 34.4 (CH2).
AP/P/ 95/00723
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-122Example 147
Ν- (2 - (4-Trifluoromethyl) phenethyl)-Ν'- (2 thiazolyl) thiourea
In a manner analogous to Example 143, using 5 4-trifluoromethyIphenylacetonitrile, the titled product resulted.
1H-NMR (CDCI3 + CD3OD) δ 7.57 (d, J = 8.3 Hz, 2H,
TFMPh), 7.40 (d, J = 8.3 Hz, 2H, TFMPh), 7.19 (d, J =
3.7 Hz, IH, thiazole), 6.83 (d, J = 3.7 Hz, IH, thiazole), 3.95 (t, J = 7.2 Hz, 2H, CH2NH), 3.08 (t, 2H,
CH2 ) ·
Example.148
LRS) -N- (2_-Methy 1--2- (2.6-difluoro)phenethyl) -Ν’ -(215 thiazol y.l). thiourea
2,6-Difluorobenzyl cyanide (1.24 ml, 10 mmole) was reacted with sodium hydride (360 mg, 12 mmole) in THF (5 ml) for 2 hour. Then iodomethane was added to the reaction mixture. After 30 min, the reaction mixture was worked up and the product was isolated by silica gel column chromatography. Yield 985 mg (59 %).
^K-NMR (CDCI3) δ (Mixture of two stereoisomers) 7.28 (m,
IH, DFPh), 6.98 (m, 2H, DFPh), 4.26 (m, IH, CH), 1.69 and 1.66 (2 x s, 3H, CH3).
In a manner analogous to Example 143, using 2methyl-2-(2,6-difluoro,phenethylamine, the titled
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-123e · ^-H-NMR (CDCI3) δ R and S stereomixture), 7.12 (m, 2H, DFPh, thiazole), 6.85 (t, 2H, DFPh), 6.77, 6.76, 6.75, 6.74 (2d, J = 3.6 Hz, IH, thiazole), 4.11 (m, IH, CH), 4.05-3.65 (m, 2H, CH2), 1-45, 1.42, (2s, 3H, CH3).
Example 149
N- (2- (2-Bromo) -phene thYll--.Hi^i2L:-£hiazQlyl)· thiourea
In a manner analogous to Example 143, using 2-bromophenylacetonitrile, the titled product resulted. 1H-NMR (DMSO-dg) δ 2.9 (t, PhCH2, 2H), 3.05 (t, PhCH2, 2H), 3.8 (q, CH2N, 2H), 7.1 (d, thiazole, IH), 7.15-7.6 (mult, o, m, p, thiazole, 5H,.
Example.. 15Q
N-(2-(l-Phenvl-l-cvclopropane)ethvl)-N1-(2thiazolvl) thiourea
In a manner analogous to Example 116, using 1 phenyl-1-cyclopropanecarbonitrile, the titled product resulted.
1H-NMR (CDCI3) δ 1.0 (d), 3.8 (d), 6.9 (d), 7.2 - 7.4 (m), 7.9, 9.5 (NH).
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Example 151
H-12- (2,6-Dimethoxv)phenethv!) -Ν' - (2-thiazolvl) thiourea
The starting material 2,6-dimethoxyphenethylamine was prepared from 2,6-dime thoxybenzaldehyde. Reaction with nitromethane according to the procedure described in Vogel, Textbook of Practical Organic Chemistry, p. 176 (Longman 1978, 4th Ed.) yialded 2,6-dimethoxy-S-nitrostyrene. This comound (1.1
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-,24g, 5.3 mmole) was dissolved in diethyl ether/tetrahydrofuran (2:1, 200 ml) and lithium aluminium hydride (0.5 g, 13 mmol) was added in small portions. The mixture was refluxed for 120 minutes and then treated with 0.6 ml H2O, 0.6 ml 15 % NaOH (aq, and
1.8 ml H2O. The mixture was filtered and purified by acid-base partitioning (NH4OH (aq) HCl dil. (aq,) and evaporated. The crude product 2,6dimethoxyphenethylamine was pure enough to be used 10 directly in the following reaction where it was condensed with the product of Example 103, in a manner analogous to Example 105, to give the titled product. iH-NMR (DMSO-dg) δ 2.9 (t, PhCH2, 2H), 3,7 (q, CH2N,
2H) , 3.8 (s, OCH3, 6H), 6.7 (d, ο, 2H, , 7.1 (d, thiazole, IH), 7.2 (t, ρ, IH), 7.3 (d, thiazole, IH)).
Example 152
N - (2 - (3.5-Dimethoxv)phenethyl)-N1 - (thiazolvl) thiourea
In a manner analogous to Example 151 the 2j product of Example 103 was condensed with 3,5dimethoxyphenethylamine, obtained from 3,5dimethoxybenzaldehyde, to result in the titled product. i-H-NMR (DMSO-dg) δ 2.8 (t, PhCH2, 2H) , 3.65 (s, OCH3,
6H) , 3.7 (q, CH2N, 2H,, 6.3 (t, ρ, IH), 6.4 (t, Ο, 2H),
7.1 (d, thiazole, IH), 7.3 (d, thiazole, IH).
Example 153
N-(2-(3.5-Dichloro)phenethvl)-N*-(2-thiazolvl)thiourea
In a manner analogous to Example 151, the
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-125dichlorophenethylamine, obtained from 3,5dichlorobenzaldehyde.
iH-NMR (DMSO-dg, δ 2.9 (t, PhCH2, 2H), 3.8 (q, CH2N,
2h), 7.1 (d, thiazole, IH,, 7.3 (mult, o and ρ, 3H), 7.4 (d, thiazole, IH,.
Example 154
N-(2-(2.5-Dichloro-6-hvdrcxv)Phenethyl)-Ν' -(2thiazolvl) thiourea
In a manner analogous to Example 151, the product of Example 103 was condensed with 2,5-dichloro6-hydroxyphenethylamine, obtained from 2,5-dichloro-6hydroxybenzaldehyde.
iH-NMR (CDC13, δ 3.0 (t, PhCH2, 2H), 3.9 (q. CH2N, 2H,,
6.9 (d, o, IH), 7.1 (d, thiazole, IH), 7.2 (d, ρ, IH),
7.3 (d, thiazole, IH).
Example 155
N=(2,3. 6-Trichloro)Phenethyl)-Ν' -(2-thiazolvl)thiourea
In a manner analogous to Example 151, the product of Example 103, was condensed with 2,3,6trichlorophenethylamine, obtained from 2,3,6trichlorobenzaldehyde.
Ικ-NMR (DMSO-dg) δ 3.3 (t, PhCH2, 2H, , 3.4 (q, CH2N,
2H) , 7.1 (d, thiazole, IH), 7.4 (d, thiazole, IH), 7.57.5 (mult., m and ρ, 2H).
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-126Example 156
Ν- (2 - (2,3,4-Trifluoro)phenethyl) -Ν - (2thiazolyl]thiourea
In a manner analogous to Example 151, the product of Example 103 was condensed with 2,3,4trifluorophenethylamine, obtained from 2,3,4trifluorobenzaldehyde, to result in the titled product. !h-NMR (CDCI3) 6 3.0 (t, PhCH2, 2H) , 4.0 (q, CH2N, 2H) ,
6.8 (d, thiazole, 2H), 6.85-7.0 (mult., m and ο, 2H),
7.2 (d, thiazole, IH) .
Example 157
N- (2 -f 2.3.5-Trichloro) phenethyl)-N'- (2thiazolyl] thiourea
In a manner analogous to Example 151, the product of Example 103 was condensed with 2,3,5trichlorophenethylamine, obtained from 2,3,5trichlorobenzaldehyde.
1H-NMR (DMSO-dg) 6 3.05 (t, PhCH2, 2H), 3.9 (q, CH2N,
2H), 7.1 (d, thiazole, IH), 7.4 (d, thiazole, IH), 7.5 (d, o, IH), 7.7 (d, p, IH).
Example 158
N-(2- (2,4-Pimethoxv)Phenethyl) -Μ.·',- (2-thiazolvl) thiourea
In a manner analogous to Example 151, the product of Example 103 was condensed with 2,4-dimethoxyphenethylamine, obtained from 2,4-dimethoxybenzaldehyde.
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-127^H-NMR (CDCI3 + CD3OD) δ 7.23 (d, J = 3.6 HZ, IH, thiazole), 7.10 (d, J = 7.8 Hz, IH, DMPh), 6.81 (d, 3.6 Hz, IH, thiazole), 6.44 (s, IH, DMPh). 6.42 (d, IH,
DMPh), 3.87 (t. 2H, CH2NH), 3.80 (s, 3H, OMe), 3.79 (s, 3H, OMe), 2.94 (t, 2H, CH2).
13C-NMR (CDCI3 + CD3OD) δ 177.3 (C=S), 161.6 (thiazole),
159.7 (DMPh), 158.4 (DMPh), 137.5 (thiazole), 130.9 (DMPh), 119.1 (DMPh), 110.9 (thiazole), 103.8 (DMPh),
99.3 (DMPh), 55.3 (OMe), 55.1 (OMe), 45.5 (CH2), 28.7 (CH2)·
Example 159
N- (2- (2.3-Dimethoxy)phenethyl)-N1 - (2-thiazolvl) thiourea
In a manner analogous to Example 151, the product of Example 103 was condensed with 2,3-dimethoxyphenethylamine, obtained from 2,3-dimethoxybenzaldehyde. ^H-NMR (CDCI3) δ 7.23 (d, J = 3.7 Hz, IH, thiazole),
7.02-6.83 (m, 3H, DMPh), 6.79 (d, J = 3.6 Hz, IH, thiazole), 3.99 (q, J = 8.9 Hz, 2H, CH2NH), 3.87 (s, 3H, OMe), 3.86 (s, 3H, OMe), 3.05 (t, 2H, 0¾).
13C-NMR (CDCI3) δ 177.3 (C=S), 161.6 (thiazole), 152.6 (DMPh), 147.3 (DMPh), 137.3 (thiazole), 132 (DMPh),
123.7 (DMPh), 122.2 (DMPh), 110.9 (thiazole), 110.8 (DMPh), 60.6 (OMe), 55.5 (OMe), 45.8 (CH2), 28.9 (CH2).
Example 160
Nr (2-(2^3, 5., 6-Tetra fluoro) ph ene thvl) -N* - (2thiazolvl)thiourea
In a manner analogous to Exaaple 151, the product of Example 103, was condensed with 2,3,5,6AP/P/ 9 5 / 0 0 7 2 3
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-128tetrafluorophenethylamine, obtained from 2,3,5,6tetrafluorobenzaldehyde.
l-H-NMR (CDCI3 + CD3OD) δ 7.24 (d, J = 3 Hz, IH, thiazole), 6.98 (m, H-F coupling, IH, TFPh), 6.83 (d, J 5 = 3 Hz, IH, thiazole), 3.99 (t, J = 6.8 Hz, 2H, CH2NH),
3.18 (t, J = 6.9 Hz, 2H, CH2).
13C-NMR(CDCl3) δ 178.2(C=S), 161.5(thiazole),
147.6(m,TFPh), 143.6(m,TFPh), 137.3(thiazole),
117.6(t,TFPh), 111.1(thiazole), 104.3 (t,TFPh),
53.3(CH2), 43.7(CH2).
Example 161
N-(2 - (2-Methoxv-5-bromo)Phenethyl)-N'- (2thiazolvl)thiourea
In a manner analogous to Example 151, the product of Example 103 was condensed with 2-methoxy-5bromophenethylamine, obtained from 2-methoxy-5bromobenzaldehyde.
J-H-NME (CDCI3) δ 7.34 (m, 3H, MBPh and thiazole), 6.81 (d, J = 3.6 Hz, IH, thiazole), 6.72 (d, J = 8.4 Hz, IH,
MBPh), 3.95 (q, 2H, CH2NH), 3.79 (s, 3H, OMe), 2.98 (t,
J = 6.8 Hz, 2H, CH2).
Example 162
N- (2- (2-Ethoxy)phenethyl) -Ν' - (2-thiazolvl) thiourea
In a manner analogous to Example 151, the product of Example 103, was condensed with 2ethoxyphenethylamine, obtained from 2-ethoxybenzaldehyde.
AP/P/ 95/00723
RAD original d rf'· k *
APOOO388
-129i-H-NMR (250 MHz, CDCI3) δ 7.37-7.16 (m, 2H, arom.), 7.22 (d, IH, CH=CH), 6.91-6.78 (m, 2H, arom), 6.78 (d, IH, CH=CH), 4.07-3.93 (2xq, 2x2H, CH2-NH, CH2-O), 3.04 (t,
2H, Ph-CH2), 1.42 (t, 3H, OCH2CH3) .
ISc-NMR (250 MHz, CDCI3) 6 178, 162, 157, 138, 131, 128, 127, 120, 111, 111, 63, 46, 30, 15.
Mp: 140°C.
Anal. Calcd. for C14H17N3OS2: C, 54.6; H, 5.5; N, 13.7. Found: C, 54.4; H, 5.6; N, 13.3:
Example 163
N- (2- (2.3-Dichloro)Phenethyl) -N· - (2-thiazolvl) thiourea
In a manner analogous to Example 151, the product of Example 103 was condensed with 2,3-dichloro15 phene thy Iamine, obtained from 2,3-dichlorobenzaldehyde.
1H-NMR (250 MHz, DMSO) δ 7.55 (d, IH, CH=CH) , 7.42-7.32 (m, 3H, arom), 7.12 (d, IH, CH=CH), 3.86 (q, 2H, CH2NH,, 3.12 (t, 2H, Ph-CH2, .
13C-NMR (250 MHz, DMSO) δ 178, 162, 138, 130, 129, 128,
112, 44, 33.
Example 164
N- 12- (4 - chlorophenvl) ethvl) -N' - f 2 - (4.5-dimethyl) thiazolvl 1
A solution of 1-[ (2-(4,5-dimethyl]thiazolyl) thiocarbamoyl] imidazole (10 nmol) and 2-(4chlorophenyl)ethylamine (1.55 g, 10 mmol) in Ν,Νdimethylformamide (30 mL, was stirred at 90eC for 1 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCI, water, saturated sodium bicarbonate, and brine. The organic layer
AP/P/ 9 5 / 0 0 7 2 3
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-130was concentrated and the residue recrystallized from ethyl acetate to provide 2.44 g (75%) of the titled product.
IR (KBr, cm1) 3170, 3024, 1550, 1510, 1260, 1212, 708;
XH NMR (300 MHz, DMSO-dg) δ 11.45 (br s, IH), 9.8 (br s,
IH), 7.35 (d, J=8 Hz, 2H), 7.3 (d, J=8 Hz, 2H). 3.8 (m,
2H), 2.85 (t, J=7 Hz, 2H), 2.2 (s, 3H), 2.05 (s, 3H);
MS (FD) m/e 326 (M+);
UV (EtOH) 297nm (e=17467), 257nm (e=10021), 219nm (e=16075, 201nm (e=22380)).
Anal. Calcd for C14H16N3S2CI:
Theory: C, 51.60; H, 4.95; N, 12.89.
Found: C, 51.70; H, 5.07; N, 13.08.
Example 165
1-r(2-napthof 1.21thiazolyl)thiocarbamovl1 imidazole
A solution of 1,1'-thiocarbonyldiimidazole (1.8 g, 20 mmol) and 2-aminonaptho(1,2]thiazole (2.0 g, 20 mmol) in acetonitrile (150 mL) was stirred at 65eC for 24 h. The resulting precipitate was collected by filtration to provide 1.69 g (46%) of the titled product.
IR (KBr, cm-1) 3148, 2670, 1465, 736;
!h NMR (300 MHz, DMSO-dg) δ 9.2 (s, IH) 8.85 (S, IH) , 8.65 (d, J=8 Hz, IH), )8.2 (br s, IH), 8.0-7.3 (m, 5H) ;
MS (FD). m/e 309 (M+-H);
UV (EtOH) 383nm (€=8297), 244 nm (€=15160), 226 nm (€=17126) .
Anal. Calcd for C15H10N4S2:
Theory: C, 58.04; H, 3.25; N, 18.05.
Found: C, 58.13; H, 3.21; N, 18.03.
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APO00388
-131Example 166
N- f 2 -phenvl ethvl 1-Ν' -f 2-naptho fl.21 thiazolvll thiourea
A solution of 1-[(2-naptho[1,2]thiazolyl)thiocarbamoyl] imidazole (1.6 g, 5 mmol) and 25 phenylethylamine (0.62 g, 5.2 mmol) in Ν,Νdimethyl formamide (20 mL) was stirred at 90°C for 1 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 1.5 g (02%) of the titled product:
IR (KBr, cm1) 3171, 3027, 1581, 1521, 1213, 695;
XH NMR (300 MHz, DMSO-dg) 8 11.7 (br s, IH), 9.9 (br S,
IH), 8.25 (d, J=8 Hz, IH), 8.0 (d, J=8 Hz, 2H), 7.8 (d, J=8 Hz, IH) , 7.6-7.2 (m, 7H), 3.95 (m, 2H), 3.05 (t, J=7 Hz,
2H) ;
MS (FD) m/e 364 (M+);
UV (EtOH) 340nm (6=23922), 325nra (6=19262), 313nm (ε=20808), 245nm (6=39665), 209 nm (€=36141).
Anal. Calcd for C20H17N3S2:
Theory: C, 66.09; H, 4.71; N, 11.56.·
Found: C, 65.86; H, 4.84; N, 11.48.
Example 167
1-1 (2.-J 4-methyl 3 thiazolyl) thiocarbamoyl] imidazole A solution of 1,1'-thiocarbonyldi imidazole (13.37 g, 75 mmol) and 2-amino-4-methylthiazole (8.55 g, mmol) in acetonitrile (150 mL) was stirred at room temperature for 24 h. The resulting precipitate was collected by filtration to provide 14.22 g (85%) of the titled product:
IR (KBr, cm1) 3179, 2558, 1455, 1217, 737;
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APO 0 0 3 8 8
-132IH NMR (300 MHz, DMSO-dg) 6 8.55 (S, IH) 7.9 (S, IH) , 7.05 (s, IH). ), 6.9 (s, IH), 2.3 (s, 3H) ;
MS (FD) m/e 224 (M+-H);
UV (EtOH) 359nm (£=10749), 291 nm (£=8720), 202 nm (£=20498).
Anal. Calcd for C8H8N4S2:
Theory: C, 42.84; H, 3.59; N, 24.98.
Found: C, 42.90; H, 3.54; N, 24.89.
Example 168
N- (2-fl-cvclohexenvnethvl) -N‘-Γ2- LL-methvl)thiazolvll phipuzea
A solution of 1-[(2-(4-methyl]thiazolyl) thiocarbamoyl] imidazole (2.24 g, 10 mmol) and 2-(1cyclohexenyl)ethylamine (1.25 g, 10 mmol) in Ν,Νdimethylformamide (25 mL) was stirred at 90°C for 4 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 2.4 g (86%) of the titled product:
IR (KBr, cm-1) 3177, 2918, 1565, 1505, 1202, 717;
!h NMR (300 MHZ, DMSO-dg) δ 11.55 (br s, IH), 9.85 (br s, IH), 6.65 (s, IH), 5.45 (s, IH), 3.65 (m, 2H), 2.25 (m,
5H), 1.9 (m, 4H), 1.55 (m, 4H);
MS (FD) m/e 281 (M+);
UV (EtOH) 291nm (£=19178), 257nm (£=9837), 201 nm (£=16247). Anal. Calcd for C13H19N3S2:
Theory: C, 55.48; H, 6.80; N, 14.93.
Found: C, 55.40; H, 6.82; N, 14.77.
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AP000388
-133Example 169
N-f2- (2-chlorophenvl) ethvll -Ν'-ί 2- (4-methvi) thiazolvll thiourea
A solution of l-[(2-[4-methyl]thiazolyl) thiocarbamoyl] imidazole (2.24 g, 10 mmol) and 2-(2chlorophenyl)ethylamine (1.56 g, 10 mmol) in N,Ndimethylformamide (25 mL) was stirred at 90°C for 1.5 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 2.4 g (77%) of the titled product:
IR (KBr, cm1) 3163, 3012, 1584, 1214, 754, 706; iH NMR (300 MHz, DMSO-dg) 5 11.6 (br s, IH), 9.8 (br s,
IH), 7.5-7.2 (m, 4H), 6.65 (s, IH), 3.85 (m, 2H), 3.05 (t, J=7 Hz, 2H), 2.2 (s, 3H);
MS (FD) m/e 311 (M+);
UV (EtOH) 292nm (£=18641), 257nm (£=10471), 202 nm (£=24729).
Anal. Calcd for C13H14N3S2CI:
Theory: C, 50.07; H, 4.52; N, 13.47.
Found: C, 49.99; H, 4.56; N, 13.45.
Example 170
N-f 2.- (l-chlprophenyDethvll-Ν'-(2-( 4-methvl) thiazolvll thiourea
A solution of l-[(2-[4-methyl)thiazolyl) thiocarbamoyl] imidazole (2.24 g, 10 mmol) and 2-(3chlorophenyl)ethylamine (1.56 g, 10 mmol) in N,Ndimethylformamide (25 mL) was stirred at 90®C for 1.5 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl
AP/P/ 95/00723
AP 0 0 0 3 8 8
-134IR (KBr, cm'1) 3171, 3016, 1581, 1214, 761, 713;
:H NMR (300 MHz, DMSO-dg) 6 11.6 (br s, 1H), 9.85 (br s,
1H), 7.4-7.2 (m, 4H), 6.65 (s, 1H), 3.85 (m, 2H), 2.95 (t, J=7 Hz, 2H), 2.2 (s, 3H);
MS (FD) rn/e 311 (M+);
UV (EtOH) 293nm (£=18976), 257nm (£=10523), 202 nm (£=27048) .
Anal. Calcd for C13H14N3S2CI:
Theory: C, 50.07; H, 4.52; N, 13.47.
Found: C, 49.94; H, 4.48; N, 13.37.
Example 171
N-f 2- (4-chlorophenvl)ethvl1 -N‘-f 2- (4-methvl)thiazolyl1 thiourea
A solution of l-[ (2-(4-methyl]thiazolyl) thiocarbamoyl] imidazole (2.24 g, 10 mmol) and 2-(4chlorophenyl)ethylamine (1.56 g, 10 mmol) in Ν,Νdimethylformamide (25 mL, was stirred at 90eC for 1.5 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 2.52 g (81%, of the titled product:
IR (KBr, cm-1) 3170, 3022, 1562, 1215, 744, 709;
1H NMR (300 MHz, DMSO-dg) 5 11.6 (br s, 1H) , 9.85 (br s,
1H), 7.38 (d, J=8 Hz,, 2H), 7.30 (d, J=8 Hz,, 2H), 6.65 (s, 1H), 3.8 (m, 2H), 2.9 (t, J=7 Hz, 2H), 2.18 (s, 3H);
MS (FD) m/e 311 (M+);
UV (EtOH) 292nm (£=16470), 257nm (£=9506), 219nm (£=13695), 201 nm (£=20563).
AP/P/ 9 5 / 0 0 7 2 3
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APO00388
-,35Arial. Calcd for C13H14N3S2CI:
Theory: C, 50.07; H, 4.52; N, 13.47.
Found: C, 49.94; H, 4.55; N, 13.58.
Example.. 122
N.-I2- (2-methoxyphenyDethvl]-Ν' - Γ2 - (4-methyl) thiazolvll thiourea
A solution of 1-[(2-[4-methyl]thiazolyl) thiocarbamoyl] imidazole(2.24 g, 10 mmol) and 2-(210 7.ethoxyphenyl)ethylamine (1.51 g, 10 mmol) in N,Nd: methyl formamide (25 mL) was stirred at 90°C for 2 h, the reaction was cooled to room temperature and the solvent ramoved in vacuo. The residue was crystallized from ethyl acetate to provide 2.2 g (73%) of the titled product:
IR (KBr, cm*1) 3173, 3024, 1568, 1246, 1206, 750, 694;
j-H NMR (300 MHz, DMSO-dg) δ 11.55 (br s, IH) , 9.85 (br s, IH), 7.2-6.8 (ro, 4H), 6.65 (s, IH), 3.75 (m, 5H), 2.9 (t, J=7 riz, 2H) , 2.18 (S, 3H);
MS iFD) m/e 307 (M+);
UV (EtOH) 291nm (¢=18637), 259nm (¢=10786), 202 nm (¢=25565).
Anal. Calcd for C14H17N3OS2*.
Theory: C, 54.70; H, 5.57; N, 13.67.
Found: C, 54.68; H, 5.50; N, 13.46.
Example 173
M=.L2- (3 -me thoxyphenyl) ethv.Ll -N' -f 2 - (4 -methyl) thiazolyl 1 thiourea
A solution of 1-[ (2-[4-methyl]thiazolyl) thiocarbamoylJ imidazole(2.24 g, 10 mmol) and 2-(3methoxyphenyl)ethylamine (1.51 g, 10 mmol) in N,NAP/P/ 9 5 / 0 0 7 2 3 bad original
APO 0 0 3 8 8
-136dimethylformamide (25 mL) was stirred at 90°C for 3.5 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 2.73 g (89%) of the titled product:
IR (KBr, cr1) 3170, 3029, 1586, 1213, 749, 691;
!h NMR (300 MHz, DMSO-dg) δ 11.55 (br s, IH), 9.9 (br s,
IH), 7.2-6.8 tin, 4H), 6.65 (s, IH), 3.8 (m, 2H), 3.72 (s,
3H), 2.85 (t, J=7 Hz, 2H), 2.18 (s, 3H);
MS (FD) m/e 307 (M+);
UV (EtOH) 292nm (£=16935), 258nm (£=9604), 202 nm {£=27197!.
Anal. Calcd for C14H17N3OS2:
Theory: C, 54.70; H, 5.57; N, 13.67.
Found: C, 54.97; H, 5.58; N, 13.60.
Example 17,4
N-f2-(4-methoxvphenvl)ethvll-Ν'-f2-(4-methvl)thiazolyl] thiourea
A solution of 1-[(2-[4-methyl]thiazolyl) thiocarbamoyl] imidazole (2.24 g, 10 mmol) and 2-(420 methoxyphenyl)ethylamine (1.51 g, 10 mmol) in Ν,Νdimethylformamide (25 mL) was stirred at 90°C for 3 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 2.35 g (76%) of the titled product:
IR (KBr, cm-1) 3171, 3009, 1565, 1511, 1218, 720, 514;
iH NMR (300 MHz, DMSO-dg) 6 11.55 (br s, IH), 9.9 (br s,
IH), 7.2 (d, J=8 Hz, 2H), 6.9 id, J=8 Hz, 2H), 6.65 (s,
IH), 3.8 (m, 2H), 3.75 (s, 3H), 2.85 (t, J=7 Hz, 2H), 2.18 (s, 3H);
AP/P/ 9 5 / 0 0 7 2 3
APO Ο Ο 3 8 8
-137•JV (EtOH) 292nm (£=18700), 258nm (£=11165), 223nm (£=14043), 201 nm (£=25520).
Anal. Calcd for C14H17N3OS2:
Theory: C, 54.70; H, 5.57; N, 13.67.
Found: C, 54.62; H, 5.55; N, 13.69.
Example 175
N- f 2- (4-methvlphenvl)ethvlΐ-N'-f 2- (4-methyl)thiazolvl1 xhiautea
A solution of 2-(4-methylphenyl)ethyl isothiocyanate (1.0 g, 5.64 mmol) and 2-amino-4methylchiazole (0.644 g, 5.64 mmol) in N,Ndimethylformamide (20 mL) was heated to 90°C for 24 h. The solvent was removed in vacuo. The resultant solid was recrystallized from ethyl acetate to provide 0.67 g (41%) of the titled product as a white solid:
IF (KBr, cm1) 3170, 3020, 1562, 1507, 1203, 986;
XH NMR (300 MHz, DMSO-d6) δ 11.55 (br s, IH), 9.9 (br s,
IH,, 7.18 (d, J=8 Hz, 2H), 7.18 (d, J=8 Hz, 2H), 6.65 (s,
IH), 3.8 (m, 2H), 2.85 (t, J=7 Hz, 2H,, 2.26 (s, 3H,, 2.18 (s, 3H);
MS (FD, m/e 291 (M+, ;
UV (EtOH) 292nm (£=18863), 257nm (£=10889), 202 nm (£=21164).
Anal. Calcd for C14H17N3S2:
Theory: C, 57.70; H, 5.88; N, 14.42.
Found: C, 57.83; H, 5.90; N, 14.36.
AP/P/ 9 5 / 0 0 7 2 3
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AP Ο Ο Ο 3 β 8
-138Example 176
Ν-ί2-(2-methoxvphenvl)ethyl]-Ν'-f2-(5-chloro?thiazolvll thiourea
A solution of 1-[(2-[5-chloro]thiazolyl) 5 thiocarbamoyl] imidazole (1.22 g, 5.0 mmol) and 2-(2methoxyphenyl)ethylamine (0.77 g, 5.0 mmol) in Ν,Ndirrethy If ormamide (20 mL) was stirred at 90°C for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acetate to provide 0.86 g (53%) of the titled product: mp 152-156°C;
IR (KBr, cm’1) 3313, 2835, 1608, 1527, 1514, 1441, 1352,
?.5 1244, 1040;
-H NMR (300 MHz, DMSO-dg) δ 11.55 (br s, IH), 8.4 (br s,
IH), 7.4 (s, IH), 7.2-6.8 (m, 4H) , 3.74 (s, 3H), 3.68 (m, 2H), 2.8 (t, J=7 Hz, 2H) ;
MS (FD) m/e 327 (M+);
UV (EtOH) 295nm (€=14366), 261 nm (€=12558), 203 nm (€=31267).
Example 177
N-f 2- (3-methQXVPhenvl)ethvl]-Ν' -ί2-(5-chloro)thiazolvll thiourea
A solution of 1-[ (2-[5-chloro]thiazolyl) thiocarbamoyl] imidazole (1.22 g, 5.0 mmol) and 2-(3methoxyphenyl)ethylamine (0.77 g, 5.0 mmol) in N,Ndimethyormamide (20 mL) was stirred at 90°C for 2 h. The
AP/P/ 95/00723
3C reaction was cooled to room temperature, poured into ethyl
AP Ο Ο Ο 3 8 8
-139saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acetate to provide 0.86 g (53%, of the titled product: mp 106-107°C;
IR (KBr, cm’1, 3334, 2826, 1611, 1517, 1332, 1259, 1156,
1051, 777;
1H NMR (300 KHz, DMSO-dg) 8 11.6 (br s, IH), 8.4 (br s,
IH), 7.4 is, IH), 7.18 (m, IH), 6.77 (m, 3H,, 3.7 (m, 5H,,
2.8 (t, J=7 Kz, 2H);
lb MS (FD) m/e 327 (M+);
UV (EtOH, 295nm (£=13695), 260 nm (£=11987), 203 nm (£=32295) .
Anal. Calcd for C13H14N3OS2CI:
Theory: C, 47.63; H, 4.30; N, 12.81.
Found: C, 47.75; H, 4.41; N, 12.65.
Example .17 8
Ν- J2- (4-methoxyphenvl) ethvl 1-N* — Γ 2 - (5-chloro) thiazolyl 1 .thipurea
A solution of 1-[(2-[5-chloro]thiazolyl)thiocarbamoyl] imidazole (1.22 g, 5.0 mmol) and 2-(4methoxyphenyi;ethylamine (0.77 g, 5.0 mmol) in N,NdimethylformarJ.de (20 mL) was stirred at 90°C for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acet3te to provide 1.2 g (74%) of the titled product:
:np 156-158°C;
IR (KBr, cm1) 3315, 2934, 1601, 1511, 1320, 1243, 1180,
1034, 745;
AP/P/ 95/00723 bad original
AP Ο Ο Ο 3 8 8
-1403-Η FMR (300 MHz, DMS0-c?6) δ 11.6 (br s, IH) , 8.4 (br s,
IH), 7.4 (s, IH), 7.1 (d, J=8 Hz, 2H), 6.8 (d, J=8 Hz, 2H), 3.67 (s, 3H), 3.63 (m, 2H), 2.7 (t, J=7 Hz, 2H);
I!3 (FD) m/e 327 (M+);
UV (EtOH) 295nm (6=13569), 260 nm (6=12490), 223 nm (6=18432), 202 nm (6=28264).
Anal. Calcd for C13H14N3OS2CI:
Theory: C, 47.63; H, 4.30; N, 12.81.
Found: C, 47.59; H, 4.34; N, 12.53.
Example 179
N-f2-(l-cvclohexenvl)ethvl)-Ν’ -f2-(5-chloro)thiazolvll thiourea
A solution of 1-((2-[5-chloro)thiazoly), 15 thiocarbamoyl) imidazole (1.22 g, 5.0 mmol) and 2-(1cyclohexenyl)ethylamine (0.645 g, 5.0 mmol) in N,Ndimethylformamide (20 mL) was stirred at 90°C for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from methylene chloride to provide 0.83 g (55%) of the titled product:
mp 145-147 °C;
IR (KBr, cm-1) 3167, 2929, 1564, 1488, 1230, 1183, 1098,
1030, 685;
1h NMR (300 MHz, DMSO-c?6) δ 11.6 (br s, IH) , 8.4 (br s,
IH), 7.4 (s, IH), 5.4 (s, IH), 3.5 (m, 2H), 2.15 (t, J=7 Hz, 2Hi , 1.9 (m, 4H), 1.5 (m, 4H);
M3 (FD) m/e 301 (M+) ;
AP/P/ 9 5 / 0 0 7 2 3
APO00388
-141UV (EtOH) 295nm (6=14231), 259 nm (£=11275), 204 nm (£=20953) .
Anal. Calcd for C12H16N3S2CI:
Theory: C, 47.75; H, 5.34; N, 13.92.
Found: C, 47.90; H, 5.47; N, 14.21.
Example
-Benazir X-pkeav 1 -2rXhiphYdanPPin A solution of DL-phenylalanine (1.65 g, 10 mmcl), methyl N-phenyldithiocarbamate (1.85 g, 10 mmol), and triethylamine (1.4 mL, 10 mmol) in ethanol (30 mL) was heated at reflux for 5 h, the mixture was cooled to room temperature ana the solvent removed in vacuo. The residue was dissolved in ethyl acetate, washed with IN aqueous HCl and water. The organic layer was concentrated and the residue recrystallized form ethanol to provide 2.48 g (88%) of the titled product:
mp 187-189°C;
MS (FD) m/e 282 (M+) .
Example. 181
1-f (2-f 5 rbromol·. thiazolyl).thiocarbamovl! imidazole
A solution of 1,1'-thiocarbonyldiimidazole (9.9 g, 50 mmol) and 2-amino-5-bromcthiazole (8.95 g, 50 mmol) in acetonitrile (20C mL) was stirred at 50°C for 24 h. The resulting precipitate was collected by filtration to provide 5.38 g (37%) of the titled product:
1h NMR (300 MHz. DMSO-dg) δ 9.3 (s, IH), 8.25 (s, IK), 7.63 (s, 1Η), 7.43 (s, IH);
MS (FD) m/e 288, 290 <M+).
APIPI 9 5 / 0 0 7 2 3
BAD ORIGINS Q
APO 0 0 3 8 8
-142Example 182
N-f2 - (2-chlorophenvl)ethvll-Ν' -[2-(5-bromo)thiazolvll thiourea
A solution of 1-[(2-[5-bromo]thiazolyl) thiocarbamoyl] imidazole (0.72 g, 2.5 mmol) and 2-(2chlorophenyl)ethylamine (0.40 g, 2.5 mmol) in Ν,Νdimethyl formamide (15 mL) was stirred at 100 °C for 1 h.
The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue purified by chromatography on silica gel to provide 0.06 g (5%) of the titled product: TR (KBr, cm-1) 3318, 2926, 1562, 1512, 1257, 1177, 1052, 749, 687;
!h NMR (300 MHz, DMSO-dg) δ 11.6 (br s, 1H>, 8.4 (br s,
IH), 7.4-7.0 (m, 5H), 3.8 (m, 2H), 2.9 (t, J=7 Hz, 2H) ;
MS (FD) m/e 375, 377 (M+);
UV (EtOH) 291nm (ε=15522), 258 nm (£=11594), 202 nm (£=28572) .
AP/P/ 9 5 / 0 0 7 2 3
Example 183
N- F2- (3.-chi or.ophenvl) ethvlL-N'.-Γ2- (5-bromo) thiazolvll thiourea
A solution of 1-[(2-[5-bromo]thiazolyl)thiocarbamoyl] imidazole (0.72 g, 2.5 mmol) and 2-(3chlorophenyl)ethylamine (0.40 g, 2.5 mmol) in N,Ndimethylformamide (15 mL) was stirred at 100°C for 1 h.
The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue purified by chromatography
BAD ORIGINAL β
AP Ο Ο Ο 3 8 8
-143on silica gel to provide 0.36 g (38%) of the titled product: mp 141-145 °C;
IR (KBr, cm1) 3168, 3019, 1568, 1514, 1331, 1251, 1189,
787, 686;
1H NMR (300 MHz, DMSO-dg) δ 11.6 (br s, IH), 8.4 (br s,
IH), 7.44 (s, IH), 7.4-7.2 (m, 4H). 3.7 (m, 2H). 2.8 (t, J=7 Hz, 2H);
MS (FD) m/e 377, 379 (M+) ;
UV (EtOH) 296nm (€=10140), 259 nm (€=8392), 201 nm (€=23984) .
Example 184
N-(2-(4-chLorophenvl)ethvll -N‘-(2-(5-bromo)thiazolvll is thiourea
A solution of 1-((2-(5-bromo]thiazolyl) thiocarbamoyl] imidazole (0.72 g, 2.5 mmol) and 2-(4chlvrcpkenylethylamine (0.40 g, 2.5 mmol) in N,Ndimethylformamide (15 mL) was stirred at 100°C for 1 h.
The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue purified by chromatography on silica gel to provide 0.32 g (34%) of the titled product:
mp 147-150°C;
IR (KBr, cm-1) 3170, 3020, 1608, 1507, 1348, 1180, 745,
2;
1H NMR (300 MHz, DMSO-dg) δ 11.6 (br s, IH) , 8.4 (br s,
IH) , 7.44 (s, IH), 7.3 (d, J=8 Hz, 2H), 7.2 (d, J=8 Hz,
2H) , 3.7 (nt, 2H), 2.8 (t, J=7 Hz, 2H) ;
AP/P/ 9 5 / 0 0 7 2 3
AP 0 0 0 3 8 8
-144MS (FD) m/e 377, 379 (M+);
UV (EtOH) 296nm (€=14604), 259 nm (€=12656), 201 nm (€=23845).
Example.185
Ν-12- (2-methoxvphenvl) ethvl.1-Ν' - Γ2 - LS.-bromo) thiazolyl 1 thiourea
A solution of 1-[(2-[5-bromo]thiazolyl) thiocarbamoyl] imidazole (0.72 g, 2.5 mmol) and 2-(2methoxyphenyl)ethylamine (0.41 g, 2.5 mmol) in N,Ndimethylformamide (15 mL) was stirred at 100 °C for 1 h.
The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue purified by chromatography on silica gel to provide 0.38 g (41%) of the titled product:
IR (KBr, era--) 3164, 2960, 1563, 1513, 1241, 1182, 1030. 757, 682;
iH NMR (300 MHz, DMSO-d6) δ 11.6 (br s, IH), 8.4 (br s,
IH', 7.43 (s, IH), 7.4-7.0 (m, 4H), 3.73 (s, 3H) , 3.7 (m,
2H), 2.9 (t, J=7 Hz, 2H);
MS (FD) m/e 371, 373 (M+);
UV (EtOH) 291nm (€=16746), 261 nm (€=13112), 202 nm (€=31492) .
AP/P/ 9 5 / 0 0 7 2 3
AP Ο Ο Ο 3 8 8
-145Example .186
Ν- Γ2- (3-methQxyphenvl)jethvll -Ν' - f2-I5-bromo) thiazolvll thiourea
A solution of 1-[(2-[5-bromo]thiazolyl) 5 thiocarbamoyl] imidazole (0.72 g, 2.5 mmol) and 2-(3methoxyphenyl) ethylamine (C.41 g, 2.5 mmol) in Ν,Νdimethylformamide (15 mL) was stirred at 100°C for 1 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue purified by chromatography on silica gel to provide 0.53 g (57%) of the titled product':
IR (K3r, cm.-1) 3174, 1558, 1510, 1339, 1238, 1175, 1041,
785, 688;
1H NMR (300 MHz, DMSO-c?6) δ 11.6 (br s, 1H, , 8.4 (br s,
1«), 7.44 (s, 1H), 7.3-6.8 (m, 4H), 3.7 (s, 3H), 3.7 (m,
2H), 2.9 (t, J=7 Hz, 2H>;
MS (FD) m/e 371, 373 (M+);
2C UV (EtOH) 294nm (£=15068), 260 nm (£=12248), 202 nm (£=35594) .
Example 187 (4-methoxvDh£nyl)e.thvl1 -Ν' - f2- (5-bromo) thiazolvll thiourea
A solution of 1-[(2-[5-bromo]thiazolyl)thiocarbamoyl] imidazole (0.72 g, 2.5 mmol) and 2-(3methoxyphenyl)ethylamine (0.41 g, 2.5 mmol) in Ν,Νdimethylformamide (15 mL) was stirred at 100°C for 1 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water,
AP/P/ 95/0072 3
bad ORIGINAL £
APO00388
-146saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue purified by chromatography on silica gel to provide 0.42 g (45%) of the titled product:
IR (KBr, cm1) 3170, 1558, 1512, 1343, 1246, 1163, 1082,
824;
!η NMR (300 MHz, DMSO-d6) 6 11.6 (br s, IH) , 8.4 (br s,
IH), 7.44 (s, IH), 7.1 (d, J=8 Hz, 2H), 6.8 (d, J=8 Hz,
2H), 3.67 (s, 3H), 3.63 (m, 2H), 2.9 (t, J=7 Hz, 2H);
MS (FD) m/e 371, 373 (M+);
UV (EtOH) 295nm (£=15314), 260 nm (£=13349), 222 nm (£=19619), 202 nm (£=30379).
Example 188
N-I2-(1-cvclohexenvl)ethvll-Ν' -Γ2-(5-bromo)thiazolvll thiourea
A solution of 1-[(2-[5-bromo]thiazolyl)thiocarbamoyl] imidazole (0.72 g, 2.5 mmol) and 2-(1cyclohexenyl;ethylamine (0.32 g, 2.5 mmol) in N,N20 dimethylformamide (15 mL) was stirred at 100°C for 1 h.
The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from
AP/P/ 95/00723
2Ξ methylene chloride to provide 0.157 g (18%) of the titled product:
IR (KBr, cm-1) 3170, 1182, 1096, 834; !h NMR (3U0 MHz, DMSO 2928, 1559, 1510, 1478, 1344, 1228,
-cf6) δ 11.6 (br s,
IH), 8.3 (br ε ,
30 IH), 7.4 (s, IH), 5.4 (s, IH), 3. . 5 (m, 2H), 2.15 (t, J=7
Hz, 2H), 1.9 (m, 4H), 1.5 tin, 4H) ;
BAD ORIGINAL
*
AP Ο Ο Ο 3 8 8
-147MS (FD) m/e 345, 347 !Μ*);
UV (EtOH) 295nm (6=15533), 259 nm (6=11792), 201nm (6=21261).
Anal. Calcd for Ci2HigN3S2Br:
Theory: C, 41.62; H, 4.66; N, 12.13.
Found: C, 41.87; H, 4.91; N, 12.21.
Example 189
N-f 2- (1-Cvclohexer.vDethyl]-N1 - f2 - (5-bromo)pyridvl) i: thiourea
A stirred solution of 2-(1-cyclohexenyl)ethyl isothiocyanate (1.67 g, 10 mmol) and 2-amino-5bromopyndine (1.73 g, 10 mmol) in N-methylpyrrolidinone (20 mL) was heated to 100eC. After 17 h, the reaction was cooled to room temperature and poured into ethyl acetate.
The organic phase was washed with IN hydrochloric acid, water (2x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by recrystallization from ethyl acetate to provide 1.08 g of the titled product (32%) as an off-white crystalline solid:
mp 166-167°C; IR (KBr, cm-1) 3159, 2927, 1595, 1561, 1531, 1475, 1310, 1228, 1092; NMR (300 MHZ, DMSO-ds) δΐΐ. 09 (br s, IH), 10.64 (s, IH), 8.20 (d, J=2.4 Hz, IH), 7.93 (dd,
J=8.9, 2.4 Hz, IH), 7.C9 (d, J=9.0 Hz, IH), 5.47 (s, IH) ,
3.62-3.58 (m, 2H), 2.19 (t, J=6.7 Hz, 2H), 2.00-1.90 (m, 4H), 1.55-1.44 (m, 4H); MS (FD) m/e 339 (M+), 341 (M+2); UV (EtOH) 305nm (6= 14037), 274nm (6=25281).
Anal. Calcd fcr Ci4Hi8BrN3S: C, 49.42; H, 5.33; N, 12.35.
Found: C, 49.22; H, 5.28; N, 12.32.
AP/P/ 95/00723 bad ORIGINAL &
APOΟ Ο3Θ8
-148Εχample 19C
Ν- (2-Phenethvl)-Ν1 -(2-(4-methvl)pvridvl1 thiourea
A stirred solution of 2-phenethyl isothiocyanate (1.63 g, 10 mmol, 1.5 mL) and 2-amino-4-methyIpyridine 5 (1.08 g, 10 mmol) in AT-methylpyrrolidinone (20 mL) was heated to 100eC. After 16.75 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid, water (3x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by recrystallization from ethyl acetate/hexanes to provide
1.69 g of the titled product (62%) as a white crystalline solid:
mp 151-153°C; IR (KBr, cm’1) 3225, 1616, 1534, 1486, 1313,
1192, 1037;
Ir NMR (300 MHZ, DMSO-dc) δ 11.72 (br s, lH) , 10.42 (s, IH) , 7.87 (d, J=5.3 Hz, IH) , 7.31-7.15 (m, 5H), 6.88 (s, IH) ,
6.80 (d, J=5.2 Hz, IH), 3.31-3.76 (m, 2H), 2.88 (t, J=7.0 Hz, 2H), 2.20 (s, 3H); MS (FD) m/e 271 (M+) ;
UV (EtOH) 290nm (£=15080), 266nm (£= 15528), 247nm (£=
13132), 202nm (£=21819).
Anal. Calcd for C15H17N3S: C, 66.38; H, 6.31; N, 15.48.
Found: C, 66.09; H, 6.34; N, 15.71.
Example 191
N-(2-Phenethvl)-Ν' -Γ2-(4.6-dimethyl)pyridyl) thiourea
A stirred solution of 2-phenethyl isothiocyanate (1.63 g, 10 mmol, 1.5 mL) and 2-amino-4,6-dimethylpyridine (1.22 g, 10 mmol) in JV-methylpyrrolidinone (20 mL) was
3C heated to 100°C. After 16 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic
AP/P/ 9 5 / 0 0 7 2 3
BAD ORIGINAL $
APO 0 0 3 8 8
-149phase was washed with IN hydrochloric acid, water (3x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by recrystallization from ethyl acetate/hexanes to provide
1.81 g of the titled product (63%) as an off-white crystalline solid:
mp 165-167°C; IR (KBr, cm1) 3219, 1618, 1543, 1342, 1215; NMR (300 MHZ, DMSO-dg) δ 11.83 (br s, IH) , 10.35 (s, IH, ,
7.25-7.16 (m, 5H>, 6.69 (s, IH), 6.63 (s, IH), 3.88-3.82 (m, 2H), 2.89 (t, J=6.8 Hz, 2H), 2.14 (s, 3H), 2.09 (s,
3H:; MS (FD) m/e 285 (M+);
UV (EtOH) 294nm (6=17405), 266nm (6= 15904), 247nm (e= 14348), 203nm (6=23896).
Anal. Calcd for C16H19N3S: C, 67.33; H, 6.71; N, 14.72.
Found: C, 67.11; H, 6.63; N, 14.71.
Example 192
N- (2-Phenethvlj--N'-(2-(3-hvdroxv)pvridvll thiourea
A stirred solution of 2-phenethyl isothiocyanate (1.63 g, 10 mmol, 1.5 mL) and 2-amino-3-hydroxypyridine (1.19 g, 10 mmol, in N-methylpyrrolidinone (20 mL) was heated to 100°C. After 65.5 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid, water (3x, and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (5% ethyl acetate/dichloromethane to 10% ethyl acetate) to provide
1.51 g of the titled product (55%). This material was recrystallized from ethyl acetate to provide 1.05 g of the titled product as an off-white crystalline solid:
AP/P! 95/00723 bad OFU©iNAL
APO 0 0 3 0 8
-150mp 168-169°C;
IR (KBr, cm1) 3377, 1613, 1561, 1534, 1347, 1288, 1152;
XH NMR (300 MHZ, DMSO-d$) δ 11.43 (br S, IH) , 10.94 (s, IH) ,
3.32 (s, IH), 7. 54-7.52 (m, IH) , 7.28-7.14 (m, 6H), 6.90
5 6.86 (m. IH!, 3. 84-3.77 (m, 2H) , 2.90 (t, J=7.0 Hz, 2H);
MS (FD) m/e 273 (M+) ;
UV (EtOH ) 309nm (£= 17349 ) , 261nm (£= 11851), 245run (ε=
17252) , 204nm (£=23596) .
Anal. Calcd for C14H15N3OS: C, 61.51; H, 5.53; N, 15.37.
Found: C, 61.46; H, 5.52; N, 15.35.
Example
N-r 2- (2-Methoxvphenvl)ethvl1-N1 -f 2- (5-bromo) pvridvl1 thiourea
A stirred solution of N-(thioimidazoyl)-2-{2methoxyphenyl)ethyl amine (2.61 g, 10 mmol) and 2-amino-5bromopyridine (1.73 g, 10 mmol) in N,N-dimethylformamide (25 mL) was heated to 90eC. After 65 h, the reaction was cooled to room temperature and poured into ethyl acetate.
The organic phase was washed with IN hydrochloric acid (2x), water (2x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by recrystallization from ethyl acetate to provide 1.78 g of the titled product (49%) as an off-white crystalline solid:
mp 147-148°C;
IR (KBr, cm’1) 3224, 1596, 1530, 1492, 1459, 1229, 1191,
103 8;
AP/P/ 9 5 / 0 0 7 2 3
RAD ORIGINAL &
AP 0 0 0 3 θ 8
-151NMR (300 MHZ, DMSO-de) δ 11.10 (br S, IH), 10.63 (s, IH),
8.11 (d, J=2.3 Hz, IH), 7.90 (dd, J=8.9, 2.6 Hz, IH), 7.217.16 (m, 2H), 7.06 (d, J=8.9 Hz, IH), 6.94-6.83 (m, 2H), 3.78-3.73 (m, 2H), 3.72 (s, 3H) , 2.86 (t, J=6.8 Hz, 2H) ;
MS (FD) m/e 365 (M+), 367 (M+2);
UV (EtOH) 305nm (£=13279), 274nm (£=26971), 202nm (£=
28527) .
Ana’.. Calcd for CisHi6BrN3OS : C, 49.19; H, 4.40; N, 11.47. Found: C, 48.97; H, 4.36; N, 11.66.
Example. 194
N- (2-(2-Chlorothenvl)ethvlJ-N1-i2-(5-bromo)pyridvll thiourea
A stirred solution of N-(thioimidazoyl)-2-(2chlorophenyl)ethyl amine (2.65 g, 10 mmol) and 2-amino-5bromopyridine (1.73 g, 10 mmol) in Ν,Ν-dimethylformamide (20 mL) was heated to 90°C. After 64.75 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with water (4x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by recrystallization from ethyl acetate/hexanes to provide
1.52 g of the titled product (41%) as a tan crystalline so]id :
mp 160-161°C;
IR (KBr, cm'1) 3220, 1594, 1562, 1534, 1474, 1338, 1222,
1165, 1088;
AP/P/ 9 5 / 0 0 7 2 3
BAD ORIGINAL &
AP 0 0 0 3 8 8
-152*H NMR (300 MHZ, DMSO-dg) δ 11.16 (brs, IH), 10.69 (s, IH) , 8.15 (d, J = 2.2 Hz, IH), 7.93 (dd, J=8.9, 2.4 Hz, IH) , 7.417.38 (m, 2H), 7.28-7.23 (m, 2H), 7.08 (d, J=8.9 Hz, IH),
3.86-3.80 (m, 2H), 3.04 (t, J=6.9 Hz, 2H) ;
MS (FD) m/e 369 (M+), 371 (M+2);
UV (EtOH) 306nm (€= 14321), 275nm (€= 24813), 257nm (€= 16728), 201nm (€= 27700).
Anal. Calcd for Ci4Hi3BrClN3S: C, 45.36; H, 3.53; N, 11.33. Found: C, 45.13; H, 3.60; N, 11.17.
Example. .135
N-(2-Phenethv!)-N'-f 2 - (4-n-propvl)thiazolyl1 thiourea
A stirred solution of 2-phenethyl isothiocyanate (1.38 g, 8.44 mmol, 1.26 mL) and 2-amino-4-n-propylthiazole (1.2 g, 8.44 mmol) in N-methylpyrrolidinone (20 mL) was heated to 100°C. After 17 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid (2x1, water (2x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by recrystallization from ethyl acetate/hexanes to provide
1.39 g of the titled product (54%) as a yellow crystalline solid:
mp 135-137°C;
AP/P/ 95/00723
IR (KBr, cm-1) 3175, 3027, 1562, 1529, 1507, 1216;
lH NMR (300 MHZ, DMSO-dg) δ 11.50 (br s, IH), 9.93 (br s,
IH) , 7.29 '-7.15 (m, 5H), 6.60 (s, IH) , 3.79-3.73 (m, 2H),
2.85 (t, J=6.9 Hz, 2H), 2.40 (t, J=7.4 Hz, 2H), 1.53-1.41
(m, 2H) , 0.82 (t, J=7.3 Hz, 3H);
MS (FD) m/e 305 (M+);
bad original ffl
AP 0 4,0 3 β 8
-153UV (EtOH) 292nm (£= 19216), 257nm (£= 10283), 202nm (£= 20314).
Anal. Calcd for Ci5Hi9N3S2: C, 58.98; H, 6.27; N, 13.76. Found: C, 59.17; H, 6.08; N, 13.55.
Example 196
N- (2-Phenethyl) -Ν' - (2- (3,5-dichloro)pyridyl! thiourea
A stirred solution of 2-phenethyl isothiocyanate (1.63 g. 10 mmol, 1.5 mL) and 2-amino-3,5-dichloropyridine (3.26 g, 20 mmol) in N-methylpyrrolidinone (20 mL) was heated to 125*C. After 16.5 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with water (5x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (20% hexanes/dichloromethane) and then recrystallized from ethyl acetate/hexanes to provj.de 581 mg of the titled product (18%) as a white crystalline solid:
mp 102-104°C;
IR (KBr, cm'1) 3409, 3040, 1560, 1508, 1429, 1147, 1057;
XH NMR (300 MHZ, DMSO-dg) δ 10.66 (S, IH) , 8.71 (s, IH) ,
8.27 (d, J=2.2 Hz, IH), 8.12 (d, J=2.2 Hz, IH), 7.32-7.19 (m, 5H), 3.82-3.76 (m, 2H), 2.90 (t, J=7.1 Hz, 2H);
MS (FD) m/e 325 (M+), 327 (M+2);
UV (EtOH) 311nm (£=8820), 276nm (£= 16571), 257nm (ε=
13676) , 203nm (£=19245) .
Aral. Calcd for Ci4H13Cl2N3S: C, 51.54; H, 4.02; N, 12.88. Found: C, 51.32; H, 4.12; N, 12.69.
ΛΡ/Ρ/ 9 5 / 0 0 7 2 3
BAD ORIGINAL &
AP Ο Ο Ο 3 8 8
-154Example 197
Ν- (2-Phenethyl) -Ν'-f 2- (4-n-butvl) thiazolyl 1 thiourea
A stirred solution of 2-phenethyl isothiocyanate (1.63 g, 10 mmol, 1.5 mL) and 2-amino-4-n-butylthiazole (1.56 g, 10 mmol) in N-methylpyrrolidinone (20 mL) was heated to lOO’c. After 16.5 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid (2x) , water (2x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by recrystallization from ethyl acetate/hexanes to provide 1.63 g of the titled product (51%) as a yellow crystalline solid:
mp 100-102°C;
IR (KBr, cm-1) 3027, 1560, 1529, 1262, 1212;
3H NMR (300 MHZ, DMSO-dg) δ 11.52 (br s, IH) , 9.89 (br s.
IH' , 7.29-7.15 (m, 5H), 6.59 (s, IH), 3.79· -3.73 (m, 2H) ,
2.86 (t, J=6.9 Hz, 2H), 2.45- 2.40 (m, 2H), 1.50- 1.40 (m,
2H) , 1.29-1.19 (m, 2H), 0.84 (t, J=7.3 Hz, 3H) ;
MS (FD) m/e 319 (M+);
UV (EtOH) 292nm (£= 19193), 258nm (£= 10262), 203nm (ε= 20024).
Anal. Calcd for C16H21N3S2: C, 60.15; H, 6.62; N, 13.15. Found: C, 59.86; H, 6.62; N, 12.99.
Example 198
N-12r (lr.Cvcl.Qhexenvl.)e.thvll-Ν'-f2- (4-n-propvl) thiazolvll thiourea
A stirred solution of 2-(1-cyclohexenyl) ethyl isothiocyanate (1.67 g, 10 mmol) and 2-amino-4-npropylthiazole (1.42 g, 10 mmol) in N-methylpyrrolidinone
APIPI 9 5 / 0 0 7 2 3
APO00388
-155(2C mL) was heated to 100°C. After 40.5 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid (2x), water (2x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by recrystailization from ethyl acetate/hexanes to provide 1.26 g of the titled product (41%) as a yellow crystalline solid:
mp 152-153°C;
IR (KBr, cm’1) 3175, 2930, 1561, 1529, 1507, 1203;
!h NMR (300 MHZ, DMSO-dg) δ 11.49 (br s, IH) , 9.90 (br s,
IH) , 6.63 (s, IH), 5.42 (s, IH), 3.60- -3.54 (m, 2H), 2.49
2.45 (m, 2H), 2.16 (t, J = 6. 5 Hz, 2H), 1.95- -1.88 (m, 4H),
1.60- -1.43 (m, 6H), 0.84 (t, J=7.3 Hz, 3H);
MS (FD; m/e 309 (M+) ;
UV (EtOH) 292nm, 257nm, 201nm.
Anal. Calcd for C15H23N3S2: C, 58.21; H, 7.49; N, 13.58. Found: C, 58.29; H, 7.58; N, 13.37.
Example 199
Ν- Γ2-(l-Cvclohexenvl)ethy11-N‘-12-(4-n-butvl)thiazolvll .thiourea
A stirred solution of 2-(1-cyclohexenyl)ethyl isothiocyanate (1.67 g, 10 mmol) and 2-amino-4-nbutylthiazole (1.56 g, 10 mmol) in N-methylpyrrolidinone (20 mL) was heated tc 100*C. After 18 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid (2x), water (2x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by recrystailization from ethyl
AP/P/ 9 5 / 0 0 7 2 3
BAD ORIGINAL fl
AP Ο Ο Ο 3 8 8
-156acetate/hexanes to provide 1.02 g of the titled product (32%) as a yellow crystalline solid: mp 92-94°C;
IR (KBr, cm’1) 3174, 2927, 1583, 1532, 1507, 1466, 1203; 5 *H NMR (300 MHZ, DMSO-d$) δ 11.73 (br s, IH) , 10.14 (br s.
IH) , 6.86 (s, IH), 5.65 (s, IH) , 3.83-3.78 (m, 2H), 2.75-
2.70 (m, 2H5, 2.42-2.38 (m, 2H) , 2.18-2.10 (m, 4H), 1.81-
1.65 (m, 6H), 1.55-1.43 (m, 2H) , 1.08 (t, J=7.3 Hz, 3H) ;
MS (FD) m/e 323 (M+);
UV (EtOH) 292nm (6= 19266), 257nm (6= 9555), 201nm (6=
15788).
Anal. Calcd for Ci6H25N3S2: C, 59.40; H, 7.79; N, 12.99. Found: C, 59.56; H, 7.94; N, 13.00.
Example 200
N-f2- Il-Cvclohexenvl)ethvll-Ν' -f2-(4-i-propvl)thiazolvll thiourea
A stirred solution of 2-(1-cyclohexenyl)ethyl isothiocyanate (1.67 g, 10 mmol) and 2-amino-4-i20 propylthiazole (1.42 g, 10 mmol) in N-methylpyrrolidinone (20 mL) was heated to 100*C. After 15.75 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid (2x), water (2x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by recrystallization from ethyl acetate/hexanes to provide 1.01 g of the titled product (33%) as a pale yellow crystalline solid:
mp 110-112°C;
IR (KBr, cm-1) 3164, 2936, 1562, 1525, 1463, 1321, 1214;
AP/P/ 9 5 / 0 0 7 2 3
BAD ORIGINAL 0
APO 0 0 3 8 8
-157!h NMP. (300 MHZ, DMSO-dg) δ 11.50 (br s, IH) , 9.84 (br s, IH), 6.61 (s, IH), 5.41 (s, IH), 3.61-3.55 (m, 2H), 2.822.76 (m, IH), 2.17 (t, J=6.4 Hz, 2H) , 1.94-1.88 (m, 4H) ,
1.56-1.41 (m, 4H), 1.14 (d, J=6.8 Hz, 6H);
MS (FD) m/e 309 (M+);
UV (EtOH) 291nm (£= 20249), 256nm (£= 9969), 201nm (£=
15880).
Anal. Calcd for C15H23N3S2: C, 58.21; H, 7.49; N, 13.58. Found: C, 58.50; H, 7.63; N, 13.38.
1C
Example 2Q1
N-(2-Phenethvl)-Ν' -Γ2-(4-i-propvl)thiazolvll thiourea
A stirred solution of 2-phenethyl isothiocyanate (1.63 g. 10 mmol, 1.5 mL) and 2-amino-4-i-propylthiazole (1.42 g, 10 mmol) in N-methylpyrrolidinone (20 mL) was heaced to 100’c. After 17 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with N/10 hydrochloric acid (2x) , water (2x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by recrystallization from ethyl acetate/hexanes to provide 1.42 g of the titled product (46%) as a yellow crystalline solid:
mp 155-156°C;
IR (KBr, cm'1) 3172, 2962, 1581, 1525, 1467, 1350, 1290, 1210;
*H NMR (300 MHZ, DMSO-dg) δ 11.52 (br s, IH) , 9.89 (br s,
IH), 7.29-7.14 (m, 5H), 6.58 (s, IH), 3.80-3.74 (m, 2H) , 2.87 (t, J = 6.9 Hz, 2H) , 2.76-2.71 (m, IH), 1.07 (d, J = 6.8
AP/P/ 9 5 / 0 0 7 2 3
APO 0 0 3 8 8
-158MS (FD) m/e 305 (M+);
UV (EtOH) 292nm (¢= 19882), 257nm (¢= 10580), 203nm (¢= 20047) .
Anal. Calcd for C15H19N3S2: C, 58.98; H, 6.27; N, 13.76.
Found: C, 58.95; H, 6.39; N, 13.72.
Example 202
N-(2-Phenethvl)-Ν'-Γ2- ( (4-alvoxvlic acid)thiazolyl)1 thiourea
A solution of N-(2-phenethyl)-Ν'-[2-((4ethylglyoxylate)thiazolyl)] thiourea (1.30 g, 3.58 mmol) in ethanol (30 mL) was treated with IN sodium hydroxide and heated to reflux. After 1 h, the reaction was cooled to room temperature, diluted with water and washed wtih ethyl acetate (2x). The aqueous layer was acidified to pH 1 with hydrochloric acid and extracted with dichloromethane (2x). The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by triturating with ethyl acetate to yield 390 mg of the titled product (32%) as a light brown solid:
mp >170°C (d);
IR (KBr, cm-1) 3024, 1705, 1669, 1565, 1323, 1146;
1H NMR (300 MHZ, DMSO-dg) δ 12.2 (br S, IH) , 9.07 (s, IH) ,
8.01 (s, IH), 7.28-7.14 (m, 5H), 3.71-3.64 (m, 2H) , 2.84 (t, J=7.3 Hz, 2H);
MS (FD) m/e 336 (M+l);
HRMS (FAB) m/e (Mt-1) calcd 336.0477, obs 336.0474;
UV (EtOH) 284nm (£=17301), 203nm (£=18110).
AP/P/ 9 5 / 0 0 7 2 3
APO 0 0 3 8 8
-159ExampIs.2Q2
N-(2-Phenethyl)-N‘-f2-(4-methoxybenzothiazolvl)1 thiourea
A solution of 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) and 2-amino-4-methoxybenzothiazole (3.60 g, 20 mmol) in N,N-dimethylformamide (50 mL) was heated to 100° C. After 64 h, the reaction was coded to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid, saturated sodium bicarbonate solution, water (2x), and brine. The organic layer was filtered directly to provide 3.87 g of the titled product (56%) as a white solid: mp 209-211°C;
IR (KBr, ctr.-1) 3171, 2938, 1570, 1527, 1331, 1191, 1044;
NMR (300 MHZ, DMSO-dg) δ 11.88 (s, IH) , 9.86 (s, IH) ,
7.49-6.93 (m, 8H) , 3.86 (s, 3H), 3.77-3.70 (m, 2H), 2.89 (t, J-7.1 Hz, 2H);
MS (FD) rn/e 343 (M+);
HRMS (FAB) m/e (M+l) calcd 344.0891, obs 344.0884;
UV (EtOH) 290nm, 248nm, 210nm.
Example 204
N- (2-Phenethylj.-N· -(2- ((5-trifluoromethyl) -1,3,4thiadiazolvl)Ί thiourea
A solution of 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0 mL) and 2-amino-5-trifluoromethyl-1,3,4thiadiazole (3.38 g, 20 mmol) in N,N-dimethylformamide (50 mL) was heated to 100°C. After 40 h, the reaction was cooled to room temperature and poured into ethyl acetate.
The organic phase was washed with water (3x) and brine (2x). The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified
AP/P/ 9 5 / 0 0 7 2 3 bad original Q
AP ο 0 0 3 8 8
-160by flash chromatography on silica gel (5% ethyl acetate in dichloromethane) and then recrystallized from ethyl acetate co provide 171 mg of the titled product (3%) as a white solid:
mp 212-213°C;
IR (KBr, cm-1) 3336, 2788, 1629, 1534, 1494, 1398, 1327, 1148, 1038;
NMR (3 00 MHZ, DMSO-dg) δ 12.6 (br s, IH) , 8.51 (s, IH), 7.30-7.15 (m, 5H), 3.73-3.66 (m, 2H), 2.85 (t, J=7.3 Hz,
2H) ;
MS (FD) m/e 332 (M+!;
UV (EtOH) 322nm (£=5240) , 261nm (£= 11025 ) , 204nm (£=28776 ) . Anal. Calcd for C12H11F3N4S2: C, 43.36; H, 3.34; N, 16.86. Found: C, 43.20; H, 3.44; N, 16.86.
Example 205
N-(2-Phenethyl)-N‘-f2-Lil-carboxylic acid)thiazolyl)1 thiourea
A solution of N-(2-phenethyl)-Ν'-[2-(4cyano)thiazolyl] thiourea (250 mg, 0.867 mmol) in glacial acetic acid (10 mL) and 5N hydrochloric acid (10 mL) was heated to reflux. After 16 h, the reaction was cooled to room temperature, diluted with acetonitrile and concentrated to dryness (2x). The solid obtained was purified by flash chromatography on silica gel (2% acetic acid in ethyl acetate) and then recrystallized from methanoi/ethyl acetate to provide 13 mg of the titled product. The mother liquor was concentrated and triturated with ethyl acetate to provide another 34 mg of the titled product, for a total yield of 47 mg (18%) as a white solid: mp > 2 3 0 °C; ______
AP/P/ 9 5 / 00723
ORIGINAL J)
X-8571A
-161Examalfi^
Ν- (2-Phenethyll-N'--L2^16_-fluoro) -benzothiazolyl 1 thiourea
A solution of 2-phenethyl isothiocyanate (3.26 g, 20 mmol, 3.0mL) and 2-amino-6-fluoro-benzothiazole (3.36 g, 20 mmol) in dimethylsulfoxide (10 mL) was heated to
150°C. After 5 h, the reaction was cooled to room temperature and filtered. The filtrate was poured into ethyl acetate, washed with water (5x) and brine (2x) . The organic layer was concentrated and recrystallized from ethyl acetate to provide 729.5 mg (11%) of the titled product:
mp 212-213°C;
IR (KBr, cm-1) 3175, 3025, 1561, 1534, 1461, 1249, 1215;
1H NMR (300 MHz, CDCI3) δ 11.81 (br s, IH), 9.83 (br s,
IH), 7.77 (dd, J=8.7, 2.4 Hz, IH), 7.52 (br s, IH), 7.3120 7.15 (m, 6H), 3.79 tin, 2H), 2.90 (t, J=6.6 Hz, 2H);
MS (FD) m/e 331 (M+);
UV (EtOH) 310nm, 289nm, 245nm, 208nm, 201nm.
bad original
APO 0 0 3 8 8
-162IR (KBr,cm1) 3275, 1603, 1531, 1394, 1268;
1H NMR (300 MHZ, DMSO - <3$) 5 7.26-7.14 (m, 6H) , 3.71-3.65 (m, 2H), 2.87 (t, J=7.2 Hz, 2H);
MS (FD) m/e 307 (M+) ;
HRMS (FAB) m/e (M+l) calcd 309.0527, obs 309.0528;
UV (EtOH) 283nm, 260nm, 206nm.
Example .2Q£
N-(2- (1-Cvclohexenvl)ethvl)-N*-f2-(6-fluorobenzothiazolvl)1 io thiourea
A solution of 2-(1-cyclohexenyl)ethyl isothiocyanate (1.66 g, 9.93 mmol) and 2-amino-6fluorobenzothiazole (1.67 g, 9.93 mmol) in dimethyl sulfoxide (10 mL) was heated to 125°C. After 20 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid, water (3x), and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (1% ethyl acetate in dichloromethane) and then recrystallized from ethyl acetate to provide 1.04 g of the titled product (31%) as a yellow crystalline solid: mp 200-201°C;
IR (KBr, cm-1) 3451, 3177, 3044, 2924, 2832, 1560, 1533,
1462, 1215, 1198;
XH NMR (300 MHZ, CDCl3)5 10.83 (s, IH) , 10.33 (br s, IH), 7.61-7.56 (m, IH), 7.41-7.37 (m, IH), 7.17-7.10 (m, IH) ,
5.65 (s, IH), 3.87-3.81 (m, 2H), 2.38 (t, J=6.5 Hz, 2H) , 2.03-2.00 (m, 4H) , 1.67-1.52 (m, 4H);
MS (FD) m/e 335 (M+);
AP/P/ 95/00723 bad original &
APO 0 0 3 8 8
-163UV (EtOH) 301nm, 218nm, 201nm.
Anal. Calcd for C16H18FN3S2: C, 57.29; H, 5.41; N, 12.53. Found: C, 57.58; H, 5.44; N, 12.42.
Example 2Q7
N-(2-Phenethvl)-Ν'-f2-(5-chlorothiazolvl)1 thiourea
2-Amino-5-chlorothiazole hydrochloride (1.71 g, mmol; was slurried with dichloromethane and shaken with a slight excess of sodium hydroxide solution. The layers were separated and the aqueous washed with dichloromethane. The combined organics were dried over sodium sulfate, filtered and concentrated. To the resulting solid was added 2-phenethyl isothiocyanate (1.63 g, 10 mmol, 1.5 mL) and N-methyl-pyrrolidinone (20 mL,. The resulting solution was heated to 100°C. After 20 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid, water (4x>, and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (2% ethyl acetate in dichloromethane, and then recrystallized twice from 1:1 ethyl acetate/hexanes to provide 187 mg of the titled product (6%) as a light brown crystalline solid:
mp 163-1S4°C;
IR (KBr, cm-1) 3312, 3028, 2925, 1607, 1527, 1513, 1438,
1377, 1348, 1314, 1026;
!h NMR (300 MHZ, DMSO-dg) 5 11.60 (br S, IH) , 8.41 (s, IH) ,
7.39 (s, IH), 7.30-7.15 (m, 5H,, 3.70-3.63 (m, 2H), 2.82 (t, J =7.2 Hz, 2H) ;
<0 MS (FD) m/e 297 (M+), 299 (M+2);
UV (EtOH) 296nm (£=14487), 260nm (£=12442), 206nm (£=27427).
AP/P/ 9 5 / 0 0 7 2 3
SAD ORIGINAL fl
AP Ο Ο Ο 3 8 8
-164Anal. Calcd for C12H12CIN3S2: C, 48.40; H, 4.06; N, 14.11. Found: C, 48.40; H, 4.16; N, 13.85.
Example ..2 Q 8
N- f 2 7 (1 -CyclPhexenyll-ethyl .-42-((4trifluoromethyl)thiazolyl)1 thiourea
A solution of 2-(1-cyclohexenyl)ethyl isothiocyanate (1.67 g, 10 mmol) and 2-amino-4trifluoromethylthiazole (1.68 g, 10 mmol) in N10 methylpyrrolidinone (20 mL) was heated to 125°C. After 20 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid (2x), water (3x), and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (1% ethyl acetate in dichloromethane) and then recrystallized from 1:1 ethyl acetate/hexanes to provide 139 mg of the titled product (4%) as an off-white solid:
mp 153-154°C;
IR (KBr.cm-1) 3168, 2932, 1562, 1513, 1472, 1438, 1219, 1175, 1081;
1H NMR (300 MHZ, DMSO-άζ) 6 11.95 (s, IH) , 8.21 (s, IH) . .71 (s, IH), 5.41 (s, IH), 3.55-3.49 (m, 2H), 2.14 ft,
J=6.7 Hz, 2H), 1.93-1.83 (m, 4H), 1.56-1.41 (m, 4H);
MS (FD) m/e 335 (M+);
HRMS (FAB) m/e (M+l) calcd 336.0816, obs 336.0842;
UV (EtOH) 285nm (£=15215), 258nm (£=12868), 203nm (£=20271).
AP/P/ 95/00723
BAD ORIGINAL ft
APO 0 0 3 8 8
-165Example .,2.Qi
N-_L2_c( 2 -Chlorophenvl) ethvl! -N’-f2-((4trifluoromethyl)thiazolyl)1 thiourea A solution of 2-(2-chlorophenyl) ethyl amine (1.56 g, 10 mmol,1.41 mL) and N-(thioimidazoyl)-2-amino-4trifluoromethylthiazole (3.0 g, 10.8 mmol) in N,Ndimethylformamide (20 mL) was heated to 90-100°C. After 2 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid (2x), water (2x), and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (1% ethyl acetate in dichloromethane) and then recrystaiiized from 1:1 ethyl acetate/hexanes to provide 870 mg of the titled product (24%) as a white crystalline solid: mp 187-188°C;
IR (K3r,cm_1) 3169, 3018, 1569, 1512, 1245, 1220, 1154, 1133, 1080;
<4 NMR (300 MHZ, DMSO-dg) δ 11.92 (s, IH) , 8.32 (s, IH) ,
7.71 is, IH), 7.41-7.22 (m, 4H), 3.76-3.69 (m, 2H) , 2.97 (t, J=7.1 Hz, 2H);
MS (FD) m/e 3 65 (M+) ;
UV (EtOH) 2S5nm (£.=13758), 257nm (£=14164), 202nm (£=30204) .
Anal. Calcd for C13H11F3CIN3S2: C, 42.68; H, 3.03; N,
11.49. Found: C, 42.82; H, 3.14; N, 11.68.
AP/P/ 95/00723
BAD ORIGINAL Λ
AP000388
-166Example 2 IQ
N-J 2-14-Chiorophenyl) e,tbyl).T.H.:x.I-2t.f (4trilluoromethvll thiazolyl) I, thiourea
A solution of 2-(4-chlorophenyl) ethyl amine (1.56 g, 10 mmol, 1.40 mL) and N-(thioimidazoyl)-2-amino-4trifluoromethylthiazole (3.0 g, 10.8 mmol) in N,NdimethvIformamide (20 mL) was heated to 90-100°C. After 2 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid (2x), water (2x), and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (1% ethyl acetate in dichloromethane) and then recrystallized from 1:1 ethyl acetate/hexanes to provide 570 mg of the titled product (16%) as a white crystalline solid: mp 196-197°C;
IP. (KBr, cm-1) 3167, 3021, 1562, 1516, 1469, 1445, 1184, 1173, 1126, 1083;
1HNMR (300 MHZ, DMSO-dg) δ 11.91 (s, IH) , 8.27 (s, IH) ,
7.71 (s, IH), 7.32 (d, J=8.4 Hz, 2H), 7.23 (d, J=8.4 Hz,
2H), 3.72-3.65 (m. 2H) , 2.83 (t, J=7.0 Hz, 2H);
MS (FD) m/e 365 (M+);
UV (EtOH) 286nm (£=11309), 257nm (£=11445), 202nm (£=21815).
Anal. Calcd for C13H11F3CIN3S2: C, 42.68; H, 3.03; N,
11.49. Found: C, 42.87; H, 3.05; N, 11.46.
AP/P/ 95/00723 bad ORIGINAL g
AP Ο Ο Ο 3 8 8
-,67Example 211
Ν- f 2 - (3-Chlorophenvl)ethvl1-N'-f 2 - ( (4 trifluoromethyl)thiazolyl)1 thiourea A solution cf 2- (3-chlorophenyl) ethyl amine (1.5c g, 10 mmol, 1.40 mL) and N-(thioimidazoyl)-2-amino-4trifluoromethylthiazole (3.0 g, 10.8 mmol) in N,Ndimethylformamide (20 mL) was heated to 90-100°C. After 2 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid (2x), water (2x), and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (1% ethyl acetate in dichloromethane) and then recrystallized from 1:1 ethyl acetate/hexanes to provide 407 mg of the titled product (11%) as a white crystalline solid: mp 159-160°C;
IR (KBr, cm’1) 3176, 3017, 1567, 1517, 1224, 1133, 1080;
Ih NMR (300 MHZ, DMSO-dg) δ 11.93 (s, IH) , 8.28 (s, IH) ,
7.72 (s- IH), 7.33-7.17 (m, 4H), 3.73-3.67 (m, 2H,, 2.85 (t, u = ?.0 Hz, 2H);
MS (FD) m/e 365 (M+), 367 (M+2);
UV 'EtOH) 285nm (6=14175 ) , 257nm (6=14293 ) , 2C2nm (6=31514 ) . Anal. Calcd for C13HHF3CIN3S2: C, 42.68; H, 3.03; N,
11.49. Found: C, 42.72; H, 3.09; N, 11.79.
Example 212
N-F2-(2-Methoxvphenyl)ethvll-Ν'-f2- ((4tnf luoromethyl) thiazolyi) i thiourea
A solution of 2-(2-methoxyphenyl)ethyl amine (1.51 g, 10 mmol, 1.46 mL) and N-(thioimidazoyl)-2-amino-4AP/P/ 9 5 / 0 0 7 2 3
AP ο Ο Ο 3 8 8
-168trifluoromethylthiazole (3.0 g, 10.8 mmol) in Ν,Νdimethylformamide (20 mL) was heated to 90-100°C. After 2 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid (2x), water (2x), and brine. The organic layer was dried ever sodium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (2% ethyl acetate in dichloromethane) and then recrystallized from 1:1 ethyl
1C acetate/hexanes to provide 872 mg of the titled product (24%) as a white crystalline solid: mp 13 4 -18 4.5 °C ;
IP 'KEr, cm'1) 3168. 2973, 1571, 1514, 1244, 1221, 1168, 1127, 1077;
-H NMR (300 MHZ, DMSO-dg) δ 11.87 (s, 1H), 8.24 (s, 1H) ,
7.71 (s, 1H;, 7.18-7.10 (m, 2H) , 6.94-6.82 (m, 2H), 3.74 (s, 3H) , 3.63-3.61 (m, 2H), 2.80 (t, J=7.0 Hz, 2H!;
MS (FD) m/e 361 (M+,;
UV (EtOH) 280nm (£=16781), 259nm (£=15202), 203nm (£=32863 > .
Anal. Calcd for C14H14F3N3OS2: C, 46.53; H, 3.90; N, 11.63. Found: C, 46.52; H, 3.94; N, 11.52.
Example,213
N-L2- i3-MethQXVE>henvl) ethvll-N* - f2- ((425 trif luoromebhyL·).thiazolyl) 1 thiourea
A solution of 2-(3-methoxyphenyl)ethyl amine (1.51 g, 10 mmol, 1.45 mL) and N-(thioimidazoyl,-2-amino-4trifluoromethylthiazole (3.0 g, 10.8 mmol) in N,Ndimer.hyl lormainide (20 mb) was heated to 90-100°C. After 2 h, the reaction was cooled to room temperature and poured
C 2 L 0 0 / ς 6 /d/dV
ΑΡ ο 0 0 3 8 8
-169hydrochlonc acid (2x) , water (2x) , and brine. The organic layer was dried over scdium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (2% ethyl acetate in dichloromethane) and then reorystallized from 1:1 ethyl acetate/hexanes to provide 1.32 g of the titled product (36%) as a white solid:
m.p i39-140°C;
IR (KBr, cm-1) 3215, 3018, 1598, 1582, 1544, 1490, 1299, 1242, 1180, 1081;
1H NMR (300 MHZ, DMSO-dg) δ 11.93 (s, IH), 8.26 (s, IH), .71 (s, IH) , 7.18 (t, J=8.0 Hz, IH), 6.79-6.74 (m, 3H), 3.73-3.66 (m, 2H), 3.69 (s, 3H), 2.80 (t, J=7.0 Hz, 2H);
MS (FD) m/e 361 (M+);
UV’ (EtOH) 281nm (6=15384) , 258nm (6=14389 ) , 202nm (6=3 5020 ) . Anal. Calcd for C14H14F3N3OS2: C, 46.53; H, 3.90; N, 11.63. Found: C, 46.76; H, 3.91; N, 11.52.
Example 214
N- (2-(4-Methoxvphenvl)ethvl1-N1 -f2-((4trifluoromethvl)thiazolvll1 thiourea A solution of 2-(4-methoxyphenyl)ethyl amine (1.51 g, 10 mmol, 1.46 mL) and N-(thioimidazoyl)-2-amino-4trifluoromethylthiazole (3.0 g, 10.8 mmol) in N,Ndirr.ethylformamide (20 mL) was heated to 90-100°C. After 2
AP/P/ 95/00723 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid (2x), water (2x), and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by flash
AP Ο Ο Ο 3 8 8
-170χθ dichlorcmethane) and then recrystallized from 1:1 ethyl acetate/hexanes to provide 893 mg of the titled product (25%) as a white crystalline solid:
mp 169-170°C;
IR 'KBr, cm-1·' 3173, 3025, 1565, 1515, 1240, 1181, 1127, 1033 ;
1H NKF (300 MHZ, DMSO-dg) δ 11.90 's, IH) . 8.26 (s, IH) ,
7.71 (s, IH) , . 12 (d, J=8.5 Hz, 2H) , 6.83 (d, J=8.5 Hz, 2K), 3.67 (s, 3H), 3.67-3.61 (m, 2H), 2.76 it, J=7.1 Hz,
2H) ;
MS (FD) m/e 361 (M+);
UV 'EtOH! 284nm (6=15865) , 258^9(6=148^2), 224nm (6=16821) , 201nm (6=29323 i .
Anal. Calcd for C14H14F3N3OS2: C, 46.53; H, 3.90; N, 11.63. Found: C, 46.70; H, 3.89; N, 11.50.
Example,., 215.
N- (2- (1-CvclQhexenvD ethvl 1 -Ν' - f 2- ((4,5flimethyllrhi.azQlv.il 1., thiourea 2-Amino-4,5-dimethylthiazole hydrochloride (1.65 g, 10 mmol) was slurried with dichloromethane and shaken with a mixture of sodium hydroxide/saturated sodium bicarbonate solution. The organics were washed with brine, dried over sodium sulfate, filtered and concentrated. To the resulting solid was added 2-(1-cyclohexenyl)ethyl isothiocyanate (1.67 g, 10 mmol) and Λ’-methylpyrrolidinone (20 mb). The resulting solution was heated to 105° c. After 20 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN. hydrochloric acid (2x), water (2x), and brine. The organic layer was dried over sodium sulfate, filtered and
AP/P/ 55/00723 bad ORIGINAL
AP Ο Ο Ο 3 8 8
-171concentrated. The solid obtained was purified by recrystallization from 2:1 ethyl acetate/hexanes to provide 1.57 g of the titled product (53%) as a light yellow crystalline solid:
mp 162-164°C;
IR (KBr, cm’1) 3170, 2917, 1583, 1554, 1514, 1433, 1325, 1255, 1215;
ΣΗ NMR (300 MHZ, DMSO-dg) δ 11.35 (s, IH) , 9.83 (br s, IH) ,
5.43 (s, IH). 3.58-3.52 (m, 2H) , 2.17-2.11 (m, 5H), 2.07 (s, 3H), 1.94-1.89 (m, 4H) , 1.57-1.44 (m, 4H) ;
MS (FD) m/e 295 (M+);
UV (EtOH) 297nm (£=18557), 256nm (£=9443), 201nm (£=16880). Anal. Calcd for C14H21N3S2: C, 56.91; H, 7.16; N, 14.22. Found: C, 57.10; H, 7.28; N, 14.36.
Example 216
N- f2- (3-Ethoxv-4-methoxvphenvl)ethvl 1 -N' - (2-thiazolvl) thiourea
A solution of 2-(3-ethoxy-4-methoxyphenyl)ethy 1 amine (1.00 g, 5.12 mmol) and N-(thioimidazoyl)-2aminothiazole (1.08 g, 5.12 mmol) in N,N-dimethyIformamide (20 mL) was heated to 90-100°C. After 16 h, the reaction was cooled to room temperature and poured into ethyl acetate. Tne organic phase was washed with IN hydrochloric acid (2x), water (2x), and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by recrystallization from dichloromethane/ethyl acetate to provide 471 mg of the titled product (27%) as an off-white solid:
mp 150-152°C;
AP/P/ 9 5 / 0 0 7 2 3
BAD ORIGINAL d
APO 0 0 3 8 8
-172IR (KBr, cm1) 3176, 3112, 3040, 1575, 1514, 1469, 1261,
1235, , 1140, 1042;
3H ID IR (300 MHZ, DMSO-dg) δ 11.51 (s, IH) , 9.73 (br s, IH)
7.23 (d, J=3.6 Hz, 1 Η), 7.07 (s, 1H> . 6. 90-6.7 8 (m, 2H) ,
6.72 (d, 0 = 8.2 Hz, IH), 4.00-3.88 (m, 2H) , 3.80 -3.67 (m,
5H) , 2.76 (t, 0=6.9 Hz, 2H) , 1.25 (t, J=6 .9 Hz, 3H) ;
MS (FD) m/e 337 (M+) ;
UV (EtOH) 287nm (€=21828) , 259nm (€=11770) , 205nm (€=35881) . Anal. Calcd for C15H19N3O2S2: C, 53.39; H, 5.67; N, 12.45. Found: C, 53.10; H, 5.64; N, 12.22.
Example 217
N- f2- (3-Methoxy-4-isopropoxyphenvl)ethvll -Ν' - (2-thiazolvl) thiourea
A solution of 2-(3-methoxy-4-isopropoxyphenyi)ethyl amine (1.00 g, 4.78 mmol) and N(thicimidazoyl)-2-aminothiazole (1.00 g, 4.78 mmol) in Ν,Νdimethylformamide (20 mL) was heated to 90-95°C. After 24 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid (2x', water (2x), and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by recrystallization from ethyl acetate to provide 891 mg of the titJed product (53%) as yellowish needles. A sample was recrystallized a second time from ethyl acetate: mp 140-141°C;
IR (KBr, cm'1, 3165, 2971, 1560, 1516, 1466, 1266, 1182,
114 4;
AP/P/ 9 5 / 0 0 7 2 3
AP Ο Ο Ο 3 8 8
-173ΧΗ NMR {300 MHZ, DMSO-dg) δ 11.53 (s, ΙΗ) , 9.71 (br s, ΙΗ) ,
7.28 (d, J=3.6 Hz, IH) , 7.06 (s. IH), 6.84-6.81 (m, 2H)
6.71· -6.68 (m, IH), 4.45-4.37 (m. IH), 3.74-3.66 (m, 5H)
2.77 (t, J=7.0 Hz, 2H) , 1.17 (d. J=6.0 Hz, 6H);
MS (FD) m/e 351 (M+);
UV (EtOH) 286nm, 258nm, 204nm.
Anal. Calcd fcr C16H21N3O2S2: C, 54.68; H, 6.02; N, 11.96. Found: C, 54.79; H, 6.11; N, 12.21.
Example 218
N-.f2- (3., 4-dichlorophenylJfithvll -Ν' - (2-thiazolvl) thiourea
2- (3,4-Dichlorophenyl) ethyl amine hydrochloride (1.00 g, 4.41 mmol) was slurried in dichloromethane and shaken with a slight excess of sodium hydroxide solution.
The layers were separated and the organics were dried over sodium sulfate, filtered and concentrated. Νί thioimidazoyl) -2-aminothiazole (928 mg, 4.41 mmol) and V, v-dirr.ethylformamide (20 mL) were added to the resulting oil. This solution was heated to 90-100°C. After 18 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid (2x), water (2x), and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (2% ethyl acetate/dichloromethane) to provide 1.0 g of 3 (68%) as a white solid. This solid was recrystallized from ethyl acetate to provide 700 mg of the titled product as a white £ I L 0 0 / g 6 /d/dV
AP Ο Ο Ο .3 8 8
-174IR (KBr, cr.’1) 3175, 1577, 1515, 1472, 1328, 1190, 1029;
ΧΗ NMR (300 MHZ, DMSO-dg) δ 11.55 (s, IH) , 9.63 (br S, IH) , 7.54-7.48 (m, 2H) , 7.30-7.21 (m, 2H), 7.06 (s, IH), 3.773.70 (m, 2H), 2.87 (t, J=6.9 Hz, 2H);
MS (FD) m/e 331 (M+);
UV (EtOH) 289nm (6=19623) , 265nm (6=11818) , 204nm (6=36059 ) . Anal. Calcd fcr C12H11CI2N3S2: C, 43.38; H, 3.34; N, 12.65 Found: C, 43.14; K, 3.36; N, 12.63.
Example 219
N-f2-(2-methvl-3-trifluoromethvlphenvl)ethvll-Ν' -(2thiazolvl) thiourea
2-(2-Methyl-3-trifluoromethyIphenyl)ethyl amine hydrochloride (1.00 g, 4.17 mmol) was slurried in dichloromethane and shaken with a slight excess of sodium hydroxide solution. The layers were separated and the organics were dried over magnesium sulfate, filtered and concentrated. N-(thioimidazoyl)-2-aminothiazole (877 mg, 4.17 mmol) and Ν,Ν-dimethylformamide (20 mL) were added to the resulting oil. This solution was heated to 90-100°C.
After 65 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid (2x), water, and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (2% ethyl acetate/dichloromethane) and then recrystallized from ethyl acetate (1st crop) or 1:1 ethyl acetate/hexanes (2nd crop) co provide 581 mg of the titled product (40%) as a white
AP/P/ 95/00723
AP Ο Ο Ο 3 8 8
-175mp 153-159cC;
IR (KBr,cm'1) 3178, 3130, 2994, 1566, 1514, 1473, 1321,
1161, 1120; XH NMR (300 MHZ, DMSO-dg) 5 11.60 (S, IH), 9.76 (br S, IH)
c 7.52-7.47 (m, 2H), 7.33-7.28 (m, 2H), 7.07 (s. IH) , 3.75-
3.68 (m, 2H) , 2.98 (t, J=7.4 Hz, 2H), 2.40 (s, 3H) r
MS (FD) m/e 345 (M+);
UV (EtOH) 289nm (£=19176), 258nm (£=11507), 203nm (£=21953). Anal. Calcd for C14H14F3N3S2: C,48.68; H,4.O8; N,12.16.
Found: C,48.89; H,4.06; N,12.14.
Example 220
Ν-Γ2- (3-13-trifluorp)propvlphenvl)ethvll -Ν' -(2thiazalYl), thiourea
2-(3-(3,3,3-trifluoro)propylphenyl)ethyl amine tosylate (1.00 g, 2.57 mmol) was slurried in dichloromethane and shaken with a slight excess of sodium hyd-cxid® solution. The layers were separated and the aqueous was extracted with dichloromethane. The combined organics were dried over magnesium sulfate, filtered and concentrated. N-(thioimidazoyl)-2-aminothiazole (540 mg, 2.5 mmol) and N,N-dimethylformamide (20 mL) were added to the resulting oil. This solution was heated to 90-95°C. After 1 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid (2x), water (2x), and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by
AP/P/ 9 5 / 0 0 7 2 3
APO 0 0 3 8 8
-1765C8 mg of the titled product (55%) as an off-white crystalline solid: mp 138-139°C;
IR 'CHC13, cm’1) 3192, 3058, 2979, 1567, 1514, 1259, 1139; 5 1H NMR (300 MHZ, DMSO-dg) 511.53 (s, IH), 9.73 (br s, IH) ,
7.29-7.06 (m, 6H) , 3.75-3.63 (m, 2H), 2.83 (t, J=7.0 Hz, 2H), 2.77-2.71 (m, 2H! , 2.57-2.45 (m, 2H);
MS !FDj m/e 359 (M+);
UV (EtOH) 288nm (£=19255) , 257nm (£=11152 ) , 203nm (£=21782 ) .
Anal. Calcd for Ci5Hi6F3N3S2: C, 50.13; H, 4.49; N, 11.69.
Found: C, 50.36; H, 4.45; N, 11.46.
Ekfl.TPle 221
N- (2-(1-Cvclohexenvl)ethvl)-Ν' -f2-pvridvl1. thiourea
A solution of 2-(1-cyclohexenyl)ethyl isothiocyanate (1.67 g, 10 mmol) and 2-aminopyridine (941 mg, 10 mmol) in N-methylpyrrolidinone (20 mL) was heated to 100°C. After 16.5 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with water (4x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by recrystallization from ethyl acetate to provide 1.31 g of the titled product (50%) as a white crystalline solid:
mp 153-155°C;
I?. (KBr, cm'1) 3219, 2921, 1605, 1569, 1537, 1481, 1319,
AP/P/ 9 5 / 0 0 7 2 3
AP Ο Ο Ο 3 8 8
-1771Η NMR (300 MHZ, DMSO-dg) δ 11.55 (s, IH) , 10.47 (s, IH) , <5.09 (d, J = 3.9 Hz, IH/, 7.74-7.68 (m, IH) , 7.09 (d, J = 8.3 Hz, IH), 7.00-6.96 tin, IH) , 5.47 (s, IH) , 3.65-3.59 tin, 2H), 2.19 It, J=6.6 Hz, 2H), 1.94-1.90 (m, 4H) , 1.55-1.43 tin. 4H) ;
MS (FD) m/e 261 (M+);
UV 'EtOH) 292nm (£=15926), 265nm (£=17724), 247nm (£=15198). Anal. Calcd for C14H19N3S: C, 64.33; H, 7.33; N, 16.08. Found: C, 64.12; H, 7.33; N, 15.89.
lO
Example 222
N- (2-ohenethvl)-Ν' -(2-(5-bromo)pvridvl) thiourea
A solution of 2-phenethyl isothiocyanate (1.63 a, 10 mmol, 1.5 mL) and 2-amino-5-bromopyridine (1.73 g, 10 mmol) in N-methylpyrrolidinone (20 mL) was heated to 100°C.
After 22 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN’ hydrochloric acid (2x) , water f2x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by recrystallization from ethyl acetate/hexanes to provide 1.2C g of the titled product (36%) as a white crystalline solid :
mp 160-162°C;
IR (KBr, cm’1) 3C28, 1595, 1559, 1531, 1475, 1311, 1228,
1092;
NMR (300 MHZ, DMSO-dg) δ 11.16 (s, IH) , 10.65 (s, IH) ,
8.11 (d. J = 2.1 Hz, IH), 7.93-7.90 (m, IH), 7.29-7.18 (m,
5H), 7.05 (-1, J=8.8 Hz, IH) , 3.82-3.77 (m, 2H) , 2.88 (t,
-.7 = ^.0 Hz, 2H);
AP/P/ 95/00723
BAD ORIGINAL
AP Ο Ο Ο 3 8 8
-178MS (FD) m/e 335 (Mr), 337 (M+2);
UV (EtOH) 305nm (£=14171), 275nm (£=24881), 201nm (£=21601). Anal. Calcd for C;4Ki4BrN3S: C, 50.01; H, 4.20; N, 12.50. Found: C, 49.93; H, 4.19; N, 12.52.
Example 223 nllT-Cyclohexenvl) ethvll.zNl-lJl- (5-cvano) Pvridyl 1 thiourea
A stirred solution of 2-(1-cyclohexenyl)ethyi isothiocyanate (1.36 g, 8.14 mmol) and 2-amino-5cyanopyridine (0.97 g, 8.14 mmol) in N-methylpyrrolidinone (20 mL) was heated to 100°C. After 5 days, the reaction was cooled to room temperature and poured into EtOAc. The organic phase was washed with H2O (4x) and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (2% EtOAc/CH2Cl2), followed by recrvstailization with EtOAc/hexanes tc provide 78 mg of the titled product !3%' as an off-white solid:
mp 195-197°C;
IR (KBr, cm’1) 2927, 2224, 1605, 1570, 1533, 1487, 1369, 1228, 1165;
ΖΗ NMR (300 MHZ, DMSC-dg) δ 11.17 (br s, IH), 10.96 (s,
IH), 8.57 (d, J=1.9 Hz, IH), 8.12 (dd, J=8.8, 2.1 Hz, IH),
7.20 (d, J=8.8 Hz, IH) , 5.47 (s, IH), 3.66-3.59 (m, 2H) ,
2.20 (t, J=6.6 Hz, 2H-, 1.94-1.89 (m, 4H), 1.54-1.43 (m,
4H) ;
MS (FD) m/e 286 (M*);
UV (EtOH) 308nm, 202nm.
Anal. Calcd for C15H16N4S: C, 62.91; H, 6.34; N, 19.56. Found: C, 62.70; H, 6.42; N, 19.42.
AP/P/ 95/0072 5 bad original
AP ο ο Ο 3 8 8
-179Example 224
Ν- '.2-phenethvl) -Ν' -Γ2- (4^.(.4_-biphenvl) thiazolvl 1 thiourea
A solution of 2-phenethyl isothiocyanate (0.82 g, 5 mir.ol, 0.75 mL) and 2-amino-4-(4-biphenyl) thiazole (1.26 g, 5 mmol) in N,N-dimethylformamide (12.5 mL) was heated to 1GO°C. After 19.5 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic solution was washed with IN hydrochloric acid. The mixture was filtered and the filtrate was separated and the organic phase washed with saturated sodium bicarbonate solution, water (4x, and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The material was purified by flash chromatography on silica gel (1% ethyl acetate in dichloromethane to 2% ethyl acetate in dichloromethane' to provide 372 mg of the titled product (18%; . The yellow solid was recrystallized from ethyl acetate:
mp 208.5-209’C;
IR K3r, cm'1) 3437, 3172, 3029, 1570, 1553, 1511, 1211, 1060, 738;
2-H NMR (300 MHz, DMSO-dg, 5 11.72 (s, IH) , 9.54 (br s, IH) , 7.85-7.80 (m, 2H), 7.78-7.68 (m, 4H), 7.58 (s, IH), 7,527.44 (m, 2H) , 7.41-7.35 (m, IH) , 7.34-7.25 (nt. 4K) , 7.277.20 ’.m. IH), 3.92-3.84 (m, 2H) , 2.98 (t, J=3 Hz, 2H) ;
MS fFL·' m/e 415 (K+>;
JV : EtOH) 293nm, 212nm.
Anal. Calcd for C24H21N3S2: C, 69.36; H, 5.09; N, 10.11.
AP/P/ 9 5 / 0 0 7 2 3
APODO 088
-180ExaiQBlg .225
N- :2-Phenethylj-N1-2-f4-(4-pvridvl)thiazolyll thiourea
2-Amino-4-(4-pyridyl)thiazole hydrobromide was slurried with methylene chloride and shaken with saturated sodium bicarbonate solution. The layers were separated and the aqueous washed with methylene chloride and ethyl acetate. The combined organic layers were concentrated. To the solid (l.C g, 5.6 mmol) was added 2-phenethyl isothiocyanate (0.91 g, 5.6 mmol, 0.83mL) in N,N1) dimethylformamide (12.5 mL). The resulting suspension was heated to 100°C. After 20.5 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with water (4x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The resulting solid was recrystallized from ethyl acetate (3x) to provide 133 mg (7%) of the titled product;
mp 196.5°C;
IR (KBr·, cm4) 3250, 2939, 1723, 1604, 1506, 1223, 670,
664 ;
Ifi NMR. (300 MHz, DMSO-dg) δ 11.72 (s, lH) , 9.21 (br s, IH) , 6.54 id, J = 6 Hz, 2H), 7.82 (s, IH) , 7.63 (d, J=6 Hz, 2H), 7.30-7.15 (m, 5H; , 3.84-3.77 (m, 2H!, 2.89 (t, J=7 Hz, 2H); MS (FD) m/e 340 (M+);
HRMS (FAB) m/e (M+) calcd 341.0895, obs 341.0909;
IT/ (EtOH) 294nm (6=23935), 231nm (6=16356), 2O3nm (6 = 25793).
AP/P/ 95/00723
ΑΡ ο Ο Ο 3 8 8
-181Examplg .22£
Μ-(2-Phenethyl) -Ν'-2-(4-(1- (1-sthvoxycarbonvl)- (3-CbutQXYcarbtmylm&thoxY.) imino) thiazolyl thiourea
2-Amino-4-(1-(1-ethoxycarbonyl)- (3-:5 butoxycarbonylmethoxy)imino)thiazole (2.64 g, 8 mmol) and
2-phenethyl isothiocyanate (1.31 g, 8 mmol, 1.2 mL) in N,Nd/methylformamide (20 mL) were heated to 100°C. After 24 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid, saturated sodium bicarbonate solution, water (3x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The resulting solid was triturated with ethyl acetate to provide 801 mg (20%) of the titled product:
mp 188.5°C;
IR (KBr, cm-1) 3293, 2975, 1749, 1594, 1543, 1453, 1382, 1231, 1154, 1054, 748, 698;
-H NMR (300 MHz, DMSO-dg) δ 11.85 (s, IH) , 8.46 (br S,1H), 7.29-7.17 (m, 5H) , 4.59 (s, 2H), 4.31-4.24 (q, J=7.1 Hz,
2H), 3.70-3.64 (m, 2H), 2.82 (t, J=7.1 Hz, 2H) , 1.36 (s,
9H), 1.23 (t, J= 7.1 Hz, 3H);
MS (FD! m/e 492 (M+);
LT/ (EtOH) 292nm, 257nm (€=16356), 203nm.
Anal. Calcd for ^22^28^405^2- 0, 53.64; H, 5.73; N, 11.37.
Found: C, 53.6^; H, 5.83; N, 11.34.
Example 227
N- (2-Phenethyll-Ν'-2- f4-t-butvl-5-methvlthiazolvlI thiourea
2-Amino-4-t-butyl-5-methylthiazole (1.87 g, 11
AP/P/ 95/00723 mmol, and 2-phenethyl isothiocyanate (1.80 g, 11 mmol, 1.64 mL) in N, N-dimethylformamide (25 mL) were heat ed to 100°C.
AP Ο Ο Ο 3 8 8
-182After 18.5 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid, saturated sodium bicarbonate solution, water (3x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The resulting solid was triturated with ether to provide 1.02 g (28%) of the titled product:
mp 153-153.5’C;
IP. (KBr, cm1) 3171, 2966, 1474, 1534, 1510, 1455, 1346,
1221, 1186, 755, 704;
!h NMR (300 MHz, DMSO-dg! 6 11.28 (BR S, IH), 9.90 (BR S,
IH) , 7.28-7.14 (Μ. 5H), 3.78-3.34 (Μ, 2H) , 2.84 (T, J = 7 Hz, 2H), 2.27 (s, 3H!, 1.16 (s, 9H);
MS (FD) m/e 333 (M+);
UV (EtOH) 297nm (£=19835), 257nm (£=9954), 202nm (£=21059).
Anal. Calcd for C17H23N3S2: C, 61.22; H, 6.95; N, 12.60. Found: C, 61.42; H, 6.92; N, 12.55.
Example 228 *0 N- (2-Phenethyl) -N.’-2-f4 - (4-bromopher.vl) -5-ethvlthiazolvl) thiourea
2-Anino-4-(4-bromophenyl)-5-ethylthiazole (848 mg, 3 mmol) and 2-phenethyl isothiocyanate (490 mg, 3 mmol, 0.45 mL) in N,N-dimethylformamide (7.5 mL) were heated to
100°C. After 22.5 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with IN hydrochloric acid, saturated sodium bicarbonate solution, water (3x) and brine. The organic layer was dried over sodium sulfate, filtered and
AP/P/ 95/00723
AP ο ο Ο 3 β 8
-133ethyl acetate and toluene to provide 146 mg (11%) of the titled product: mp 169-170°C;
IR (KBr, cm-1) 3165, 3025, 2969, 2530, 1581, 1558, 1520,
1234, 1158, 1009;
XH NMR '300 MHz, DMSO-dg) 5 11.54 (s, IH), 9.40 (br 3, IH), 7.57 (d, J=8.3 Hz, 2H), 7.36 (d, J = 8.3 Hz, 2H), 7.21-7.14 (m, 5H) , 3.75-3.73 (m, 2H) , 2.87-2.82 (m, 2H), 2.80 (q, J=7.8 Hz, 2H), 1.17 (t, J=7.8 Hz, 3H);
MS (FD) m/e 445 (M+), 447 (M+2);
UV (EtOH) 291nm, 263nm, 237nm, 203nm.
Anal. Calcd for C20H20BrN3S2: C, 53.81; H, 4.52; N, 9.41; Found: C, 53.71; H, 4.61; N, 9.39.
Example,, .222
N-(2-Phenethv!)-Ν' -i2-pvridinof 2.3-dithiazolyl thiourea
A solution of 2-phenethyl isothiocyanate (1.33 g, 8.13 mmol, 1.21 mL) and 2-aminopyridion[2,3-d]thiazole (1.23 g, 8.13 mmol) in Ν,Ν-dimethylformamide (15 mL) was heated to 105°C. After 46.5 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic solution was washed with water (6x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The material was purified by flash chromatography on silica gel (5% ethyl acetate in dichloromethane to 10% ethyl acetate in dichloromethane) to provide 330 mg of the titled product (13%). The white powder was recystallized from ethyl acetate:
mp 202-202.5°C;
IR (KBr, cm1) 3445, 3171, 3025, 1565, 1551, 1510, 1382,
1201, 1150;
AP/P/ 9 5/ 0 0 7 ?
bad ORIGINAL ffl
AP Ο Ο Ο 3 β 8
-184j-H NMR (300 MHz, DMSO-dg) δ 11.91 ibr s, IH) , 9.76 (br s, IH), 8.37 (m, IH), 7.88 (m, IH), 7.43 (dd, J= 3 and 6 Hz, IH;, 7.33-7.20 (m, 5H), 3.82-3.79 (m, 2H), 2.89 (t, J = 7 Hz, 2H) ;
MS (FAS) m/e 315 (M+l);
UV (EtOH) 312nm (£=22468), 211nm (£=19194).
Anal. Calcd for C15H14N4S2: C, 57.30; H, 4.49; N, 17.82. Found: C, 57.20; H, 4.49; N, 17.66.
Example ,23Q
N- (2-Phenethvl) -N..'.-ethvl) pyridvll thiourea
A) 2-t-ButoxvcarbonvlaminQ-3-ethvlPvridine
2-t-Butoxycarbonylaminopyridine (10 g, 51.5 nmoi) was dissolved in tetrahydrofuran (80 mL), and cooled to -78° C. N-butyllithium (80 mL of 1.49 M in hexanes,
120 mmol) was added dropwise over a period of 1 h. After stirring for an additional 15 min at -78°C and then for 2.5 hour- at -10°C. the solution w^s then recooled back down to -78°C and iodoethane (77.2 mmol, 6.18 mL) was added
2; dropwise over a period of 15 min via syringe. The solution was allowed to warm to room temperature. The reaction was quenched with 100 mL of a saturated ammonium chloride and extracted with ethyl acetate (3x). The organic layers were collected, dried over magnesium sulfate, and concentrated.
Tne resulting solid was purified by flash chromatography on silica cel :25% ethyl acetate/hexanes) to provide the 4.9 g (43%) of the titled product as a light brown solid: mp 101-102cC;
IR (KBr,cm-1) 3174, 2968, 1725, 1594, 1519, 1442, 1278,
1249, 1156;
AP/P/ 95/00723
AP Ο Ο Ο 3 8 8
-185+ Η ΝΜ?. (300 MHZ , DMSO-dg) δ 8.98 (s, 1 Η) , 8.17 (m, ΙΗ) . 7.61 (m, 1ΚΙ , 7.15 (m, 1Κ). 2.52 (q, J=7.5 Hz, 2Η) , 1.39 (s, 9Η), 1.08 (t, J=7.5 Hz, 3H) ;
MS (FD) m/e 222 (M+);
UV (EtOH) 270nm (ε= 4398) , 223nm (ε= 6745 ) .
Anal. Calcd for Ci2HisN2O2: C, 64.84; H, 8.16; N, 12.60. Found: C, 64.91; H, 8.34; M, 12.42.
b; Preparation, .af 3-Ethvl-2-aminopyridine.
2-t-Butoxycarbonylamino-3-ethylpyridine (4.9 g, 19.8 mmol! was dissolved in 90 ml of 3N HCl/Acetic acid and stirred for two hours. The sloution was neutralized with 2N NaOH to pH 7 and then extracted with ethyl acetate (2x 400 ml). The organics were dried over magnesium sulfate and concentrated giving 2.3 g (95%) of a yellowish solid. This solid was used in the next reaction without further purification.
C) N-(2-Phenethvl)-Ν' -f2-(3-ethvl)pvridvl1thiourea
A solution of phenethyl isothiocyanate (3.61 g,
18.8 mmol, 3.3 mL) and 2-amino-3-ethyIpyridine (2.3 g, 18.8 mmol) in Ν,Λ’-dimethy If ormamide (20 mL) was stirred at 9095°C for 3 h. The solution was cooled to room temperature, poured into ethyl acetate (150 mL), and washed with 0. IN hydrochloric acid (2x), water (3x), and brine. The organics were dried over sodium sulfate, filtered, and concentrated. The resulting solid was purified by flash chromatography on silica gel (1.5% ethyl acetate/dichloromethane) and then recrystaiiized (30% ethyl
AP/P/ 9 5 / 0 0 7 2 3
BAD ORIGINAL A
APO 00 388
-186acetate/ hexanes) to give l.lg (21%' of the titled product as a white solid : mp 57-58°C;
IR (KBr, cm'1) 3433, 2932, 1561, 1516, 1452, 1433, 1328,
1237, 760;
TH NMR (300 MHZ, DMSO-dg) δ 11.58 (br s, IH), 8.66 (s, IH), 7.30-7.15 (m, 5H),
2.89 (t, J=6 Hz, 2H), 5 Hz , 3 H) ;
7.92-7.90 (m, IK), ^.6-7.58 (m, IH) ,
7.02-6.98 (m, IH), 3.83-3.77 (m. 2H;
2.64 (q, J=7.5 Hz, 2H), 1.09 (t, J=7
MS (FD) m/e 285 (M+);
UV (EtOH) 2?3nm (ε= 16632), 265nm (£= 14930), 244nm (£= 16594), 202nm (£= 21127) .
Anal. Calcd for C16H19N3S: C, 67.33; H, 6.71; N, 14.72.
Found: C, 67.17; H, 6.88; N, 14.51.
Exairplg., 2,3.1
N- (2-Phenethvl) -Ν’. - £2^-13-bromo)pvridvl 1 thiourea
a) 2-^7guLaxycaE)2gnYlflmiDQ.-.3..-]?rQingpyridirie
2-t-Butoxycarbonylaminopyridine (10 g, 51.5 mmol) was dissolved in tetrahydrofuran (80 mL), and cooled to -78° C . N-butyllithium (120 mmol, 80 mL of 1.49 M in hexanes) was added dropwise over a period cf 1 h . After stirring for an additional 15 min at -78°C and then for 2.5 h at -10°C, the solution was recooled back down to -78°C and 1,2-dibromoethane (77.2 mmol, 6.65 mL) was added dropwise over a period of 15 min via syringe. The solution was allowed to warm to room temperature. The reaction was quenched with 100 ml, of saturated ammonium chloride and was extracted with ethyl acetate !3x). The organic layers were collected, dried over magnesium sulfate, filtered, and
AP/P/ 95/00723
BAD ORIGINAL
AP Ο Ο Ο 3 8 8
-187concentrated. The resulting solid was purified by flash chromatography on silica gel (25% ethyl acetate/hexanes) giving 4.5 g (32%) of the titled product as a light brown solid:
mp 120-12i°C;
IR (KBr, cm’1) 3191, 2980, 1729, 1521, 1442, 1365, 1272, 1166, 1032;
NMR (300 MHZ, DMSO-dg) δ 9.28 (s, IH) , 8.34 (m, IH) , 8.05 (m, IK), 7.15 (m, IH), 1.39 (s, 9H) ;
MS (FD) m/e 272 (M+), 274 (M+2);
UV (EtOH) 280nm (ε= 4047) , 230nm (ε= 9067) , 204nm (ε= 16385) .
B) Preparation of 3-BromQ-2-aminopvridine.
3-Bromo-2-t-butoxycarbonylaminopyridine (3.8 g,13.9 mmol) was dissolved up in 70 ml of 3N HCl/ Acetic acid and stirred for two hours. The solution was neutralized with 2N NaOH to pH 7 and then extracted with ethyl acetate (3x 300 ml). The organics were dried over magnesium sulfate and concentrated giving a brown oil.
This was put on vacuum overnight giving 2.4 g (100%) solid crystals. This was used in the next reaction without further purification:
mp 57-59’C;
NMR (300 MHZ, DMSO-dg) δ 7.9 (m,lH), 7.65 (m,lH), 6.527. 6.4 (m,lH), 6.2-6.1(s, 2H) .
Ci N-(2-Phenethyl)-N'-F2-(3-bromo)pvridvl1 thiourea
A solution of phenethyl isothiocyanate (1.89g, 11.6 mmol, 1.73 mL) and 2-anuno-3-bromopyridine (2.0 g,
11.6 mmol) in N,N-dimethylformamide was stirred at 90-95°C
AP/P/ 9 5 / 0 0 7 2 3
AP Ο Ο Ο 3 8 8
-138pourec into ethyl acetate (150 mL) , and washed with 0. IN hydrochloric acid (2x) , water (3x), and brine. The organics were dried over sodium sulfate, filtered, and concentrated. The resulting solid was purified by flash chromatography cn silica gel (30% ethyl acetate/hexanes) to yield 0.5 g (13%) of the titled product as a white solid: mp ?5-96°C;
IR (KBr, cm’1) 3403, 3021, 1591, 1564, 1548, 1514, 1435, 1150, 750, 700;
1H NMR (300 MHZ, DMSO-dg) δ 11.2 (s, IH) , 8.45 (s, IH) ,
8.13-8.06 (m, 2H), 7.29-7.18 (m, 5H), 7.04-7.0 (m, IH), 3.86-3.8 (m, 2H), 2.91 (t, J=6 Hz, 2H);
MS 'FD) m/e 335 (M+), 337 (M+2);
UV (EtOH) 298nm (ε= 13404 ) , 272nm (ε= 16029) , 250nm (ε= 17186) ,
203nm (€=22974) .
Anal. Calcd for Ci4Hi4N3S2Br: C, 50.01; H, 4.20; N, 12.50. Found: C, 49.77; H, 4.21; N, 12.37.
Example. .23.2
2C N- (4-Bromoohenethvl)-Ν'-(2-(4-ethvl)thiazolvllthiourea
4-Bromophenethylamine hydrochloride (1 g, 4.22 mmol) was slurried with dichloromethane and water. Sodium hydroxide (0.17g, 4.22 mmol) dissolved in water was added to this mixture and stirred. The organics were separated, washed with brine, dried over sodium sulfate, filtered, and concentrated. The resulting solid was added to Νί thioimidazoyl)-2-amino-4-ethylthiazole (1.0 g, 4.22 mmol) in N, N-dimethyl-formamide (20 mL) and stirred for 3 h at
0-ur;°c. The solution was cooled to room temperature and £ I L 0 0 / G 6 /d/dV added to 150 mL of ethyl acetate, washed with 0. IN
APO 0 0 3 6 8
-189organics were dried over sodium sulfate, filtered, and concentrated. The solid was recrystallized (50% ethyl acetate/ hexanes) providing 0.7 g (45%) of the titled product as a yellow solid :
mp 156-157°C;
IR (KBr, cm’1) 2963, 1560, 1527, 1259, 1212, 1011, 802, 743;
LK NMR (300 MHZ, CDCI3) δ 10.94 (br s, IH) , 9.77 (br s,
IH), 7.41 (d, J=8.3 Hz, 2H), 7.24 (d, J=8.2 Hz, 2H) , 6.33 (s, IH), 4.03-3.97 (m, 2H), 2.97 (t, J=6.8 Hz, 2H), 2.49 (q, J=7.5 Hz, 2H), 1.13 (t, J=7.5 Hz, 3H) ;
MS (FD) m/e 369 (M+), 371 (M+2);
UV (EtOH) 292nm (ε= 10803 ) , 257nm (ε= 6300) .
Anal. Calcd for Ci4Hi6N3SBr: C. 45.41; H, 4.35; N, 11.35.
Found; C, 45.53; H, 4.42; N, 11.49.
Example 222
N- (3-Fhenoxvr»henethvl) -Ν' -(2- (4-ethvl) thiazolvll thiourea
3-Pher.oxyphenethylamine hydrochloride (1.0 g,
4.0 mmol) was slurried with dichloromethane and water.
Sodium hydroxide (0.16 g, 4.0 mmol) dissolved in water was added and stirred. The organics were separated, washed with brine, dried over sodium sulfate, filtered, and concentrated. The resulting solid was added to N25 Ithioimidazoyl)-2-amino-4-ethylthiazole (1.0 g, 4.22 mmol) in N,N-dimethyl-formamide (20 mL) and stirred for 3 h at 9O-95°C. The solution was cooled to room temperature, added to 150 rrJL cf ethyl acetate and washed with 0.1N hydrochloric acid (2x), water (3x), and brine. The organics were dried over sodium sulfate, filtered, and
AP/P/ 9 5 / 0 0 7 2 3
AP Ο Ο Ο 3 8 8
-190recrystallized (50% ethyl acetate / hexanes) providing 0.6 g (42%) of the titled product as a white solid : mp 12 4 °C ;
IR (KBr, cm1·) 3177, 2966, 1563, 1534, 1509, 1491, 1446,
1349, 1287, 1250, 1218, 1158, 773;
l-H NMR (300 MHZ, CDCI3) δ 10.99 (br s, IH) , 9.87 (brs, IH) , 7.21-7.23 (m, 3H), 7.09-6.84 (m, 6H), 6.32 (s, IH), 4.033.97 (m, 2H), 2.99 (t, J=6.8 Hz, 2H), 2.53 (q, J=7.5 Hz,
2H), 1.14 (t, J=7.5 Hz, 3H);
MS (FD) m/e 383 (M+);
UV (EtOH) 293nm (€= 19262), 258nm (ε= 11356) , 205nm (ε= 37212) . Anal. Calcd for C20H21N3OS2: C, 62.63; H, 5.52; N, 10.96. Found: C, 62.69; H, 5.61; N, 11.06.
Example 234 ), -N 12.- t^rethylJ£hiaz.Qlyl.l.thigurea
2-Nitrophenethylamine tosylate (0.97g, 3.0 mmol) was slurried with dichloromethane and water. Sodium hydroxide (0.12 g, 3 mmol) dissolved in water was added and soirred. The organics were separated, washed with brine, dried over sodium sulfate, filtered, and concentrated. The resulting solid was added to N-(thioimidazoyl)-2-amino-4ethylthiazole [BK8-6TT-074] (0.71 g, 3 mmol) in Ν,Νdimethylformamide (20 mL) and stirred for 3 h at 90-95°C.
The solution was allowed to cool to room temperature and then was added to 150 mL of ethyl acetate and washed with 0. IN hydrochloric acid (2x), water (3x), and brine. The organics were dried over sodium sulfate, filtered, and concentrated. The solid was recrystallized (50% ethyl acetate/ hexanes) providing 0.5g (54%) of the titled product as a white solid :
AP/P/ 9 5 / 0 0 7 2 3 bad original
AP Ο Ο Ο 3 8 8
-191ιηυ 132-133°C;
IR (KBr, cm'1) 3171, 2966, 1586, 1531, 1509, 1341, 1215;
Ih NMR (300 MHZ, CDCl3)5ll.O6 (br s, IH) , 9.76 (br s, 1H) , 7.98 (d, J = 8.1 Hz, IH), 7.56-7.35 (m, 3H) , 6.35 (s, IH),
4.13-4.02 (m, 2H!, 3.33 (t, J=7 Hz, 2H,, 2.56 (q, J=7.4 Hz,
2H!, 1.16 (t, J=7.4 Hz, 3H);
MS 'FD'i m/e 336 (M+);
UV ;EtOH) 232nm (£=20546) , 258nm (ε= 14748) , 2O3nm (£= 24932 ) . Anal. Calcd for Ci4Hi6N4°2s2: C, 49.98; H, 4.79; N, 16.65.
Found; C, 49.95; H, 4.86; N, 16.59.
Example 235
N- f 6- (2-PhenvlbenzQxazDlen e..thvJJ -N‘-f2ethvlthiazolvllthiourea
2-[6-(2-phenylbenzoxazole)] ethylamine hydrochloride (0.88 g, 3.2 mmol) was slurried with di chloromethane and water. Sodium hydroxide (0.13 g, 3.2 mmol) dissolved in water was added and stirred. The organics were separated, washed with brine, dried over sodium sulfate, filtered, and concentrated. The resulting solid was added to N-(thioimidazoyl)-2-amino-4ethylthiazole (0.71 g, 3 mmol) in /7, JV-dimethy If ormamide (20 mL) and stirred for 3 h at 90-95°C. The solution was cooled to room temperature, added to 150 mL of ethyl acetate and washed with 0. IN hydrochloric acid (2x), water (3x), and brine. The organics were dried over sodium sulfate, filtered, and concentrated. The solid was recrystallized (50% ethyl acetate/ hexanes) providing 0.64 g (49¾) of the titled product as a white solid :
AP/P/ 95/00723
AP 0 0 0 3 8 8
-192IR (KBr, cm'1) 3178, 3035, 1578, 1533, 1506, 1253, 1214, 701;
i'rt NMR (300 MHZ, CDCI3) δ 10.96 (br s, IH) , 9.7 (br s, IH)
8.25-8.21 (m, 2H) ι , 7.69 (d, J=8 .1 Hz, IH) , 7.53 -7. 48 (m,
4H), 7.29 (m, IH) , 6.28 (s. IH) , 4.13 -4.06 (m, 2H) , 3.17
! t, J = 5.6 Hz, 2H) , 2.39 iq. J = 7 .5 Hz, 2H) , 1.0 (t, J=7.5
Hz, 3Hj;
MS (FD) m/e 408 (M+) ;
UV (EtOH) 294nm (6=12603, , 201nm (6= 14517) .
Anal. Calcd for C21H20N4OS2: C, 61.74; H, 4.93; N, 13.71. Found: C, 61.99; H, 5.18; N, 13.85.
Example 236
N-2-Phenoxyphenethvl1-N‘-Γ2-(ethvl)thiazolyl1 thiourea
2-Phenoxyphenethylamine hydrochloride (0.97 g,
3.9 mmol) was slurried with dichloromethane and water. Sodium hydroxide (0.13 g, 3.9 mmol) dissolved in water was added and stirred. The organics were separated, washed with brine, dried over sodium sulfate, filtered, and concentrated. The resulting solid was added to N(thioimidazoyl)-2-amino-4-ethylthiazole (0.929 g, 3.9 mmol) in Ν, N- dimethyl formamide (20 mL) and stirred for 3 h at 9095°C. The solution was cooled to room temperature, added to 150 mL of ethyl acetate and washed with 0.1N hydrochloric acid (2x), water (3x), and brine. The organics were dried over sodium sulfate, filtered, and concentrated. The resulting solid was recrystallized (50% ethyl acetate/ hexanes) providing 0.73 g (49%) of the titled product as a white solid :
mp 168°C;
AP/P/ 95/00723
BAD OR'GiNAL
AP Ο Ο Ο 3 8 8
-193IR (KBr, cm'1} 3168, 3013, 1581, 1532, 1487, 1237, 1209, ^53,-Η NMR (300 MHZ, CDCI3) δΐθ.93 (br s, IH), 9.67 (br s, IH) ,
7.35-7.24 (rr,, 3H) , 7.21-7.16 (m, IH) , 7.08-7.02 (m, 2H) ,
6.94-6.86 tin, 3H), 6.31 (s, IH) , 4.05-4.0 tin, 2H) , 3.05 (t,
C = 6.9 Hz, 2H), 2.5 (q, J=7.5 Hz, 2H), 1.12 (t, J=7.5 Hz,
H) ;
M3 (FE· m/e 383 (M+);
UV (EtOH) 292nm (£= 19052 ) , 258nm (ε= 11450) , 204nm (e= 38534 ) . 10 Anal. Calcd for C20H21N3OS2: C, 62.63; H, 5.52; N, 10.96.
Found: C, 62.91; H, 5.67; N, 11.22.
Example 237
N-f f (4-methyl-2-thiazolyl)aminolthioxomethyl]-DL15 phenylalanine methvl ester
A solution of 1-[(2-[4-methyl]thiazolyl) thiocarbamoyl] imidazole (0.45 g, 5.0 mmol) and DLph^nvlalarine methyl ester hydrochloride (0.43 g. 2.0 mmol) in Ν, N- dimethylformamide (50 mL) was heated at 110C for 12
h. The reaction was cooled to room temperature, solvent removed under reduced pressure, recrystallized from ethyl ether-hexanes to provide 118 mg (18%) of the titled product:
mp 131-132’C;
AP/P/ 9 5 / 0 0 7 2 3
25 IR (KBr, , cm1) 3179, 3027, 1578, 1579, 1533,1224;
1 -H NMR '3 00 MHz, DMSO-c/g) δ 11. 80 ( br s, IH), 10.20 (br
S, IH) , 7.20-7.33 (m, 5H), 6.63 (S, IH) , 5.10 (q, IH) , 3.63
1 s , 3H) , , 3.03-3.22 (m, 2H) , 2.12 (s, 3H);
MS (FD) m/e 335(M+);
UV (EtOH) 294nm (£=18428) , 257nm (£=9852) , 202nm (£=21796 i .
BAD ORIGINAL Ά
APO 0.0 3 8 8
-194Anai. Calcd for Ci5Hi7N3O232: C, 53.71; H, 5.11; N, 12.53. Found: C, 53.47; H, 5.11; N, 12.75.
.(.+ -) -3- (4-methvl-2-thiazolvl) -5- tpher.vlnethvl) -2-thioxo-4imidazglidipang
A solution of N-[((4-methyl-2thiazolyl) amino]thioxomethyl]-DL-phenylalanine methyl ester (C.94 g, 2.80 mmol! and p-toluene sulfonic acid hydrate (C.20 g 1.05 mmol) in toluene (80 mL) was refluxed with a
Dean-Stark trap for 24 h. The reaction was cooled to room temperature, solvent removed under reduced pressure, residue taken up in ethyl acetate, washed with saturated sodium bicarbonate and saturated sodium chloride, dried
1: over magnesium sulfate, and concentrated under reduced pressure. The resulting product was recrystallized from ethyl acetate-hexanes to provide 216.1 mg (25%) cf the titled product:
mp 159-171'C;
2. IR (KBr, cm’1) 3153, 1776, 1539, 1280, 1195, 744, 303;
1H NMF (300 MHz, DMSO-dg) δ 10.85 ( s, IH) , 7.40 (d, IH! , 7.30im, 3H), 7.11(m, 2H), 4.83 (t, IH) , 3.50 (d, 2Hi ,
2.35 (s, 3H);
MS (FD) m/e 3 03 (M+);
>5 oV(EtOK) 265nm (£=16902) . 203nm (£=17971) .
Anal. Calcd for C14H13N3OS2: C, 55.42; H,4.32; N,13.35. Found: C.55.63; H, 4.45; N, 13.91.
AP/P/ 9 5 / 0 0 7 2 3 bad ORIGINAL
AP 0 0 0 3 8 8
-195Example 229
N-f (Z-thiazolvlamino)thioxomethvll-DL-phenvlalanine methvl ester
A solution of 1-[(2-thiazolyl) thiocarbamoyl] imidazole (4.21 g, 20.0 mmol) and DL-phenylalanine methyl ester hydrochloride (4.31 g, 20.0 mmol) in N,Ndimethylformamide (15C mL) was heated at 90‘C for 3 h. The reaction was cooled to room temperature, solvent removed under reduced pressure, recrystalllized from ether-hexanes to provide 3.26 g (51%) of the titled product:
IR (K3r, cm’1) 3184, 3029, 1735 1569, 1510, 1223,1189 ;
!h NMR (300 MHz, DMSO-c?6) δ 11.90 (s, IH) , 7.40 (d, IH) , 7.20-7.38 (m, 5H,, 7.17 (d, IH), 5.30 (q, IH), 3.63 (s,
3H), 3.02-3.22 (m, 2H);
MS (FD) m/e 321(M+);
UV (EtOH) 291nm (£=18235), 255 nm (£=10773), 202nm (£=20575). Anal. Calcd fcr C14H15N3O2S2: C, 52.31; H, 4.70; N, 13.07. Found: C, 52.24; H, 4.61; N, 13.18.
Example 240
DL-5-(phenvlmethvl)-3-(2-thiazolyl)-2-thioxo-4Lhiazolidiapne
A solution of N-[(2-thiazolylamino)thioxomethyl]DL-phenylalanine methyl ester (0.47 g, 2.23 mmol) and ptoluene sulfonic acid hydrate (0.20 g 1.05 mmol) in toluene (50 mL) was refluxed with a Dean-Stark trap for 12 h. The reaction was cooled to room temperature, solvent removed under reduced pressure, residue taken up in ethyl acetate, washed with saturated sodium bicarbonate and saturated sodium chloride, dried over magnesium sulfate, and
AP/P/ 95/00723
AP Ο Ο Ο 3 8 8
-196was recrystallized from ethyl ether-hexanes to provide 0.243g (58%) of the titled product: mp 164-165'C;
IR (KBr, cm’1) 3099, 2985, 2873, 1775,1532, 1440, 1393,
1325, 1251, 1208, 737 ;
CM? (300 MHz, DMSO-dg) δ 10.90 ( s, IH) , 7.83 (d, IH) , 7.80 >d, IH), .50 im, 3H) , 7.20 (m, 2H), 4.90 (t, IH! , 3.17 (d, 2H);
MS (FD) m/e 239(M+);
UV (EtCH) 264nm (£=16108) , 202nm (£=17275).
Anal. Calcd for Ci3HnN3OS2: C, 53.96; H, 3.83; N,14.52. Found: C,54.22; H, 3.96; N, 14.30.
Example. 243.
N-; z2-benzothiazolvlamino) thioxomethvl1-DL-rhenvlalanine methvl ester
A solution of 1-[(2-benzothiazolyl) thiocarbamoyl] imidazole (1.30 g, 5.0'mmol) and DLphenylalanine methyl ester hydrochloride (1.08 g, 5.0 mmol) in N, N-dimethylformamide (50 mL) was heated at 90'C for 3 ti. The reaction was cooled to room temperature, solvent removed under reduced pressure, recrystalllized from ethyl ether-hexanes to provide 1.31 g (70%) of the titled product:
mp 168-i69*C; IR (KBr, cm1) 3168, 3030, 1732, 1548, 1525, 1206.1153;
-H >MR (300 MHz, DMSO-dg) 610.30 (br s, IH), 7.88 (d, IH), 7.62 id, IH), 7.32 (t, IH) , 7.20-7.29 (m, 6H), 5.18 (q, in) , 3.7Ό s, 3H), 3.22 (m, 2H) ;
AP/P/ 95/00723
MS (FD) nVe 371 (M+) :
AP Ο Ο Ο 3 8 8
-197Anai. Calcd fcr C18H17N3O2S2: C, 58.20; H, 4.61; N, 11.31. Found: C, 58.19; H, 4.70; N, 11.30.
Example 242
DL-3- (2-benzothiazolyl-) -5 ^iphenvlmethvl) -2-thioxo-4thiazolidinone
A solution of N-[(2benzothiazolylamino)thioxomethyl]-DL-phenylalanine methyl ester (1.0 g, 2.69 mmol) and p-toluene sulfonic acid hydrate (0.20 g 1.05 mmol) in toluene (80 mL) was refluxed with a Dean-Stark trap for 36 h. The reaction was cooled to room temperature, solvent removed under reduced pressure, residue taken up in ethyl acetate, washed with saturated sodium bicarbonate and saturated sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting product was recrystallized from ethyl acetate-hexanes to provide 74.9 mg (8%) of the titled product:
mp 187-189’C;
IR (KBr, cm'1) 3250, 1766, 1522, 1489;
1H NMR (300 MHz, DMSO-dg) 8 11.00 (s, 1H), 8.18 (d, 1H),
8.02 (d, 1H), 7.C8-8.00 (m, 2H), 7.37 (m, 3H), 7.23 (d,
2H), 4.97 (t, 1H), 3.18 (d, 2H) ;
MS (FD) m/e 339(M+);
UV (EtOH) 300nm (£=7355) , 265nm (£=19454 ) , 217nm (£=26558 ),
203nm (£=31150) .
Anal. Calcd for C17H13N3OS2: C, 60.16; H,3.86; N,12.38. Found: C, 60.33; H, 4.14; N, 12.25.
AP/P/ 9 5 / 0 0 7 2 3
APO 0 0 3 8 8
-198Exampls-2,43
N- f f (6-fluorc-2-benzothiazQlvJJaminQlth.iQXQmehhvlI -DLphenvlalanine methvl ester
A solution of 1-((2-[6 - fluoro]benzothiazolyl) thiocarbamoyl] imidazole (1.40 g, 5.0 mmol) and DLphenyiaianme methyl ester hydrochloride (1.0S g, 5.0 mmol) in Ν,Ν-dimethylformamide (175 mL) was heated at 90 °C for 3 n. The reaction was cooled to room temperature, solvent removed under reduced pressure, recrystalllized from ethyl ether-hexanes to provide 900 mg (46%) of the titled product:
NMR (300 MHz, DMSO-dg) δ 10.03 (br s, IH), 7.82 (q, IH),
7.60 (m, IH), 7.20-7.32 (m, 6H), 5.10 (q, IH), 3.63 (s,
3H1, 3.2U (t, 2H); MS (FD) m/e 339 (M*).
Example 244
xlvl) - 5- (phenvlmethvl.) -2-thjoxo4-imidazQliQinone
A solution of N-[[{6-fluoro-2benzothiazolyl! amino]thioxomethyl]-DL-phenylalanine methyl ester (0.90 g, 2.31 mmol) and p-toluene sulfonic acid hydrate (0.20 g 1.05 mmol) in toluene (80 mL) was refluxed with a Dean-Stark trap for 48 h. The reaction was cooled to rocm temperature, solvent removed under reduced pressure, residue taken up in ethyl acetate, washed with saturated sodium bicarbonate and saturated sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting product was recrystallized from ethyl ether-hexanes to provide 251mg (31%) of the titled product:
AP/P/ 9 5 / 0 0 7 2 3
BAD ORIGINAL ffl
AP Ο Ο Ο ό 8 8
-199mp 223-224‘ C;
IR (KBr, cm-1) 3173, 1767, 1538, 1453, 138S, 1267;
1H NMR (300 MHz, DMSO-dg) δ 11.02 (S, IH), 8.00-8.12 (m, 2H), 7.40-7.50 (m, IH,, 7.20-7.39 (m, 5H), 4.97 (t, IH, ,
3.20 id, 2H);
MS (FD) m/e 357(M*);
UV (EtOH) 265nm (£=15680), 223nm (£=19505), 201nm (£=23655). Anal. Calcd for C17H12FN3OS2: C, 57.13; H.3.38; N,11.76. Found: C,56.89; H, 3.43; N, 11.60.
Example 245
N-f f(4,5-dimethvl-2-thiazolvl) amino!thioxomethvl1-DLphenvlalanine methvl ester A solution of 1-I(2-[4,5-dimethyl]thiazolyl) thiocarbamoyl] imidazole (1.80 g, 7.5 mmol) and DLphenylaiamne methyl ester hydrochloride (1.60 g, 7.5 mmol) in AC .V-dimethyl formamide (50 mL) was heated at 90'C for 4 h. The reaction was cooled to room temperature, solvent removed under reduced pressure, recrystalllized from ether20 hexanes to provide 1.91 g (72%) of the titled product:
IR (KBr, cm’1) 3178, 3029, 1756, 1552, 1505, 1219 ;
:K NMR. (300 MHz, DMSO-dg) δ 11.65 (br s, IH! , 7.20-7.38 (m, 5H), 5.10 (q, IH), 3.65 (s, 3H,, 3.05-3.21 (m, 2H), 2.20 is, 3Hi, 2.08 (s, 3H) ;
MS (FD) m/e 349(M+);
UV (EtOH, 300nm (£=17248), 257 nm (£=9202), 2C3nm (£=22444!. Anal. Calcd for CigHi9N3O2S2: C, 54.99; H, 5.48; N, 12.02. Found: C, 55.16; H, 5.57; N, 12.01.
AP/P/ 9 5 / 0 0 7 2 3
AP Ο Ο Ο 3 8 8
-200DL-3- (4, 5-dimethvl-2-thiazolvl)-5- (chenvlmethvl! -2-thlooxo4-inudazQli.dinQns A solution of N-(4,5-dimethyl-25 thiazolyl, amino]thioxomethyi]-DL-phenylalanine (1.00 g,
2.86 mmol) and p-toluene sulfonic acid hydrate (0.20 g,
1.00 mmol.' in toluene (5C mL! was refluxed with a DeanStark trap for 48 h. The reaction was cooled to room temperature, solvent removed under reduced pressure, residue taken up in ethyl acetate, washed with saturated sodium bicarbonate and saturated sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting product was recrystallized from etnyl ether-hexanes to provide 0.545 g (60%) of the titled product:
mp 205-207‘C;
IR (KBr, cm’1) 3161, 1733, 1527, 1287, 1164;
XH NMR (300 MHz, DMSO-d6) δ 10.80 (s, IH) , 7.30 (m, 3H),
7.20 (m, 2H), 4.83 (t, IH), 3.10 (d, 2H) , 2.32 (s, 3H),
2.21 (s, 3H));
MS (FD) m/e 317 (M+);
UV (EtOH) 266nm (6=16921), 201 nm (6=17995).
Anal. Calcd for C15H15N3OS2: C, 56.76; H, 4.76; N, 13.24. Found: C, 56.53; H, 4.94; N, 13.49.
Exair-Rle-247
Nr-Ll L4--Cvanc-2-thiazolvl) amino) thioxcmethvl! -DLchenvlalanine methyl ester A solution of 1-( (2-[4-cyano]thiazolyli thiocarbamoyi] imidazole (1.76 g, 7.5 mmol) and DLphenylalanine methyl ester hydrochloride (1.62 g, 7.5 mmol) £ I L 0 0 / S 6 /d/dV
BAD ORIGINAL
APO 0 0 3 8 8
-201ιη N, N-dimethylformamide (50 mL) was heated at 90°C for 5 h. The reaction was cooled to room temperature, solvent removed under reduced pressure, recrystallized from ethyl ether-hexanes to provide 1.42 g (55%) of the titled product:
IR (KBr, cm'1: 3011, 2220, 1742, 1672, 1586,1455, 1372;
1H NMR. (300 MHz, DMSO-dg) δ 7.12-7.38 (m, 5H), 7.40 (s, IH), 5.05 (q, IH), 3.63 (S, 3H) , 3.03-3.22 (m, 2H); MS (FD) m/e 346 (M+);
UV (EtOH)287nm (ε=7404), 257nm (6=12260), 206nm (£=30014).
Example 2.,48
DL-3-(4-cvano-2-thiazolvi)-5-(phenvlmethvl)-2-thioxo-4imidazolidinone A solution of N-[((4-cyano-2thiazolyl) amino]thioxomethyl]-DL-phenylalanine methyl ester (1.42 g, 4.10 mmol) and p-toluene sulfonic acid hydrate (0.20 g 1.05 mmol) in toluene (80 mL) was refluxed with a Dean-Stark trap for 24 h. The reaction was cooled to room temperature, solvent removed under reduced pressure, residue taken up in ethyl acetate, washed with saturated sodium bicarbonate and saturated sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting product was recrystallized from ethyi ether-hexanes to provide 170.1 mg (10%) of the titled product:
mp 214-216’C; IR (KBr, cm-1) 3294, 3092, 2246, 1781, 1505, 1381, 1325, 1244 ;
^-H NMR ,500 MHz, DMSO-dg) δ 11.08 (s, IH! , 8.90 (s, IH),
7.22-7.80 (m, 3H), 7.20-7.22 (m, 2H), 4.83 (t, IH) , 3.17 (d, 2H);
APIPI 95/0072 3 bad original A
APO 0 0 3 8 8
-202MS (FD) m/e 314(M+);
UV (EtOH) 259nm (£=15097) , 205nm (£=26419) .
Anal. Calcd for C14H10N4OS2: C, 53.49; H, 3.21; N,17.82. Found: C, 53.75; H, 3.43; N, 17.62.
Ν-1f(4-trifluoromethvl-2-thiazolyl)aminolthioxomethvll-DLphenvlalanine methvl ester A solution of 1-((2-[4-trifluoromethyl]thiazolyl) thiocarbamoyl] imidazole (1.60 g, 5.8 mmol) and DLphenylalanine methyl ester hydrochloride (1.24 g, 5.8 mmol) in N, N-dimethylformamide (50 mL) was heated at 90*C for 5h. The reaction was cooled to room temperature, solvent removed under reduced, recrystaiiized ethyl ether-hexanes to provide 2.22 g (99%) of the titled product:
IR (CHCI3, cm1) 3000, 1744, 1672,1554, 1523, 1226;
XH NMR (300 MHz, DMSO-dg) δ 8.64 (d, IH) , 7.82 (s, IH) , 7.21-7.38 'm, 3H) , 7.19-7.21 'd, 2H) , 5.05 (q, IH) , 3.63 (s, 3H), 3.02-3.22 (m, 2H) ;
MS (FD) m/e 389(M+,;
UV (EtOH) 287nm (£=11327), 256nm (£=11674 ) , 203nm (£=24532 ) . Anal. Calcd for C15H14F3N3O2S2: C, 46.27; H, 3.62; N,
10.79. Found: C, 46.55; H, 3.57; N, 11.06.
AP/P/ 9 5 / 0 0 7 2 3
Example 250
£)LcJ_-.j..4-trifluojtfmethyl-2-thiazolvl) -5- (phenvlmethvl)-230 thioxo-4-imidazolidinone
AP Ο Ο Ο 3 8 8
-203Α solution of Ν-[[(4-trifluoromethyl-2thiazclyl) amino]thioxomethyl]-DL-phenylalanine methyl ester(2.09 g, 5.38 mmol) and p-toluene sulfonic acid hydrate (0.20 g 1.05 mmol) in toluene (80 mL) was refluxed with a Dean-Stark trap for 48 h. The reaction was cooled to room temperature, solvent removed under reduced pressure, residue taken up in ethyl acetate, washed with saturated sodium bicarbonate and saturated sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting product was recrystallized from ethyl ether-hexanes to provide 1.01 g (53%) of the titled product:
mp 187-189'C;
IR (CHCI3, cm1) 3431, 3008, 1782, 1495, 1369, 1328, 1242,
1178, 1149, 1085;
IH NMR (300 MHz, DMSO-dg) δ 11.02 (s, IH) , 8.59 (s, IH),
7.22-7.80 (m, 3H), 7.20-7.22 (m, 2H), 4.83 (t, IH), 3.17 (d, 2H);
MS (FD) m/e 357 (M*);
UV (EtOH) 263nm (£=13898), 202nm (£=19355).
Anal. Calcd for C14H10F3N3OS2: C, 47.05; H,2.82; N,11.76. Found: 0,47.33; H, 2.86; N, 11.67.
Example 251
N-(2-fl-cvclohexenvllethvl)-N‘-J2-(6-bromo)Dvridinvl) thiourea
A solution of 2-(1-cyclohexenyl)ethyl isothiocyanate (1.67 g, 10 mmol) and 2-amino-6bromopyiidine (1.73 g, 10 mmol) in N, N-dimethylformamide (100 mL) was heated at 100’C for 96 h. The reaction was cooled to room temperature, solvents removed under reduced
AP/P/ 9 5 / 0 0 7 2 3 bad original $
ΑΡ ο Ο Ο 3 8 8
-204pressure, taken up in ethyl acetate washed with IN HCl.
The organic layer was concentrated and the residue purified by HPLC (elution with hexanes-EtOAc) to afford 70.1 mg (2.1%) of the titled product:
mp 174-175'C;
IR (CHC13, cm1) 2936, 1592, 1512, 1448, 1203 ;
!h NMR. (300 MHz, DMSO-dg) 6 10.79 (s,lH), 10.65 (m, IH) ,
7.70 (t, IH), 7. 28 (d, IH), 7.19 (d, IH) , 5.60 (s, IH),
3.70 (q, 2H), 2. 23 (t, 2H), 1.95 (s, 4H) , 1.62- 1.42 (m, 4H)
* MS (FD) m/e 341 (M+) ;
UV (EtOH) 303nm (£=19786) , 269nm (£=18279) , 252nm (£=18006) , 201nm (£=17992) .
Anal. Calcd for Ci4Hi8BrN3S: C, 49.42 H, 5.33; N, 12.35.
Found: C, 49.69; H, 5.36; N, 12.09.
Example. 252 .2hexsLYlI.,s^.y,ll -ft’ - f ί 4--ssprppy.llpyr idinvl 1
Lhisupea
A solution of 2-(1-cyclohexenyl)ethyl isothiocyanate (0.36 g, 2.2 mmol) and 2-amino-4isopropylpyridine (0.36 g, 2.2 mmol) in Ν,Νdimethylformamide (20 mL) was heated at 100*C for 96 h.
The reaction was cooled to room temperature, solvents removed under reduced pressure, taken up in ethyl acetate, washed with IN aqueous HCl. The organic layer was concentrated and the residue purified by HPLC (elution with hexanes-EtOAc) to afford 169 mg (5.6%) of the titled
AP/P/ 9 5 / 00723 product:
mp 105-106*C;
IR (KBr, cm’1) 3215, 2931, 1614 1556, 1534, 1487, 1199;
BAD ORIGINAL tyi
AP Ο Ο Ο 3 8 8
-2053Η NMR (300 MHz, OMSO-d^) δ 11.65 (t, 1Η) , 10.40 (s, 1Η) , 8.30 (d, 1Η) , 7.20 (s, 1Η) , 6.93 (d, 1Η), 5.52 (s, 1Η) , 3.63 (q, 2Η), 2.80 (m, 1Η), 2.22 (t, 2Η) , 1.95 (m, 4Η), , 1.62-1.42 (m, 4Η), 1.18 (d, 6Η) ;
MS (FD) m/e 303 (M+);
UV (EtOH) 290nm (8=17565) , 266nm (ε=18863) , 247nm (8=15125 ) , 203ηιη(ε=23091) .
Anal. Calcd for C17H25N3S: C, 67.28;H, 8.30; N, 13.85. Found: C, 67.55; H, 8.48; N, 13.94.
Example. 253
N- (2-Jl-cvclohexenvn ethvl) -N* - (2-f 6methvlthiolbenzothiazolyl1 thiourea
A solution of 2-(1-cyclohexenyl)ethyl isothiocyanate (1.67g, 10 mmol) and 2-amino-6methylthiobenzothiazole (1.96 g, 10 mmol) in Ν,Νdimethylformamide (20 mL) was heated at 100*C for 96 h.
The ’•e?T'ion was cc<^led to room temperature, a precipitate formed,' collected, washed with ethyl acetate to provide
1.22 g (54%) of the titled product:
mp 186-187*C;
IR (KBr, cm1) 3171, 3036, 2918, 1548, 1522, 1251, 1214;
!h NMR (300 MHz, DMSO-d6> δ 11.82 (br s, IH) , 10.20 (br s, IH), 7.88 (s, IH), 7.6-7.5 (m, IH) , 7.4-7.3 (q, IH) , 5.55 (s, IK), 3.67 (q, 2H), 2.4 (s, 3H), 2.25 (t, 2H), 1.95 (s,
4H), 1.62-1.42 (m, 4H);
MS (FD) m/e 363 (M+);
UV (EtOH) 318nm (ε=14538), 256 nm (ε=6742), 224nm (ε=13749), 201 nm (ε=11940) .
£ 2 L 0 0 / g 6 /d/dV
APO 0 0 3 8 8
-206Anal. Calcd fcr C17H21N3S3: C, 56.16; H, 5.82; N, 11.56. Found: C, 56.40; H, 5.94; N, 11.76.
Example 254
Nti2-Jl-pyclphexenyLlethvIl--N,--L2·- (.4-1.4-.
bromoIphenyl)thiazolvll thiourea
A solution of 2-(1-cyclohexenyl) ethyl isothiocyanate (1.67 g, 10 mmol) and 2-amino-(4-(4brcmophenyl)]thiazole (2.55 g, 10 mmol) in N,N1? dimethylformamide (20 mL) was heated at 100*C for 72 h.
The reaccion was cooled to room temperature, solvent removed under reduced, recrystallized from ethyl acetatehexanes to provide 455 mg (11%) of the titled product: mp 219-220’C;
IR (KBr, cm1) 3171, 2927, 1566, 1516, 1301, 1211, 1071,
1110;
!h NMR (300 MHz, DMSO-dg) δ 11.70 (s, IH) , 9.30 (br s, IH) . ~.8C (d, 2H), 7.60 (m, 3H>, 5.43 (s, IH), 3.67 (q, 2H),
2.25 (t. 2H), 1.95 (s, 4H), 1.62-1.42 (m, 4H);
MS (FD) m/e 421 (M+);
UV (EtOH) 285nm (€=27781), 245 nm. (€=17426), 202nm (€=31192). Anal. Calcd for Cl8H20BrN3S2: C, 51.18; H, 4.77; N, 9.95. Found: C, 51.08; H, 4.47; N, 9.91.
AP/P/ 95/0072 3
BAD ORIGINAL &
AP Ο Ο Ο 3 8 8
-207Example 255
Ν-(2-f1-cvclohexenvl)ethvl)-N‘-f2-(4-f2(hexadecvloxv)phenvlI)thiazolvll thiourea
A solution of 2-(1-cyclohexenyl)ethyl 5 isothiocyanate (840 mg, 5 mmol) and 2-amino-4-(2[hexadecyloxy]phenyl)thiazole (2.10 g, 5 mmol) in Ν,Νdimethyl formamide (20 mL) was heated at 100 °C for 72 h.
The reaction was cooled to room temperature, solvent removed under reduced, recrystallized from ethyl acetate10 hexanes to provide 900 mg (31%) of the titled product:
mp 9 8 - 9 9’C; i*
IR (KBr, cm-1) 2919, 1567, 1473, 1222,1062, 681; C XH NMR (300 MHz, DMSO-dg) 5 11.62 (s, IH) , 9.62 (br s, IH) ,
7.95 (d·. IH), 7.56 (s, IH) , 7.30 (t, IH) , 7.12 (d, IH) ,
7.0 (t, IH), 5.43 (s, IH), 4.10 (t, 2H), 3.65 (q, 2H), 2.25 (t, 2H), 1.95 (br s, 2H) , 1.83 (t, 3H), 1.94-1.73 (m, 4H),
1.40-1.38 (m, 2H), 1.23 (s, 28H) ;
MS (FD) m/e 583 (M+);
UV (EtOH) 299nm (£=21244), 263 nm (ε=21549) , 202nm (£=30773 , .
Anal. Calcd for C34H53N3OS2: C, 69.93; H, 9.15; N, 7.19.
Found: C, 69.70; H, 8.99; N, 7.28.
Example 256
NcJ.(^-thiazQlyllaminQlthioxomeLhvl-DL.--2-fluorophenylalanine 25 meuhvl ester
A solution of 1-[(2-thiazolyl) thiocarbamoyl] imidazole (3.15 g, 15 mmol) and DL-2-fluorophenylalanine methyl ester hydrochloride (3.51 g, 15 mmol) in Ν,Νdimethyl formamide (100 mL) was heated at 80'C for 8 h. The reaction was cooled to room temperature, the solvent removed under reduced pressure, and the residue
AP/P/ n 5 ζ η n
BAD ORIGINAL
AP Ο Ο Ο 3 8 8
-208recrystallized from ethyl ether-hexanes to provide 1.89 g (37%) of the titled product:
ZR (KBr, cm-1) 3187, 3122, 3090, 3037, 2950, 1739, 1566,
1495, 1209, 1182;
NMR (300 MHz, DMSO-dg) δ 11.81 (br s, IH) , 7.39 (d, IH) ,
7.26 (ι?, 2H), 7.18 (m, 3H) , 5.16 (q, IH) , 3.64 (s, 3H, ,
3.23 (m, 2H);
MS (FD) m/e 339 (M+);
UV (EtOH· 290nm (£=18548), 256 nm (£=10899), 203nm (£=19927). 10 Anal. Calcd for C14H14FH3O2S2: C, 49.67; H, 3.87; N,
12.42. Found: C, 49.45; H, 4.07; N, 12.40.
Example ,257
DL-3- (2-thiazolvl) -5-f (2-fluoro)phenvlmethvl]-2-thioxo-415 imidazolidingne
A solution of N-[ (2-thiazolyl) amino] thioxomethylDL-2-fluorophenylalanine methyl ester (1.0 g, 2.95 mmol) and p-toluenesulfonic acid hydrate (0.20 g 1.05 mmol) in toluene (100 mL) was refluxed with a Dean-Stark trap for 48
h. The reaction was cooled to room temperature, solvent removed under reduced pressure, residue taken up in ethyl acetate, washed with saturated sodium bicarbonate and saturated sodium chloride, dried over magnesium sulfate, ar.d. concentrated under reduced pressure. The resulting
AP/P/ 9 3 / 0 0 7 2 3 product was recrystallized from ethyl acetate-hexanes to provide 305 mg (23%) of the titled product:
IR (KBr, cm' -204; !) 3104, 2870, 1781, 1531, 1438, 1330, 1255,
Lh NMR (3 00 MHz, DMSO-dg) δ 10.95 (br s, IH), 7.85 (d, IH)
30 7.78 (d, IH) , 7.30 (m, 2H) , 7.18 (m, 2H), 4.83 (t, IH) ,
3.18 id, 2H);
bad ORIGINAL
AP Ο Ο Ο 68 8
-209MS (FD) m/e 307(Μ+);
UV (EtOH)397 (ε=586) , 263nm (ε=16615) , 201nm (ε=15980)
Anal. Calcd for C13H10N2 FOS2: C, 50.80; H,3.28; 1/,13.67. Found: C, 50.84; H, 3.33; N, 13.38.
Example 258
NnI12-XhiazQlvU-aroino1thioxomethyl-DL-3.5bislrrifluorgmethvll-Phenvlalanine methvl ester
A solution of 1-[ (2-thiazolyl) thiocarbamoyl] imidazole (0.46 g, 2.19 mmol) and DL-3,5ditrifluoromethylphenylalanine methyl ester hydrochloride (0.77 g, 2.19 mmol) in N, N-dimethylformamide (75 mL) was heated at 80'C for 7 h. The reaction was cooled to room temperature, the solvent removed under reduced pressure, and the residue recrystallized from ethyl ether-hexanes to provide 203 mg (20%) of the titled product:
IR (KBr, cm’1) 3179, 3022, 1745, 1568, 1379, 1291, 1212;
1H NMR (300 MHz, DMSO-<?6) δ 11.82 (br s, IH), 7.98 (s, 3H),
7.10 (m, IH) , 5.12 (m, IH), 3.31 (s, 3H), 3.08 (m, 2H) ;
MS (FD) m/e 457(M+) ;
UV (EtOH) 291 (6=18895), 255nm (ε=10490) , 202nm (6=19571) Anal. Calcd for C16H13F6N3O2S2: C, 42.01; H, 2.86; N,
9.19. Found: C, 41.90; H, 2.74; N, 9.36.
Example 259
DL-3 - (2-thiazolvl)-5-f(3.5bis r trifluoromethyl])phenylmethylI-2-thlcxo-4imlda2olidinone
A solution of N-[(2-thiazolyl) amino]thioxomethyl30 DL-3,5-bistrifluoromethylphenylalanine methyl ester (0.15
AP/P/ 9 5 / 0 0 7 2 3
SAD ORIGINAL
AP Ο Ο Ο 3 8 8
-210g, 0.22 mr.cl) and p-tcluene sulfonic acid hydrate '0.10 g C.53 mmol) in toluene ¢65 mL? was refluxed with a DeanStark trap for 45 h. The reaction was coded tc room temperature, the solvent removed under reduced pressure, and the residue taken up in ethyl acetate, washed with saturated sodium bicarbonate and saturated sodium chloride, 'ied ever magnesium sulfate, concentrated under reduced •essure to provide 39 mg '29%) of the titled product.
T?. (KBr , cm. 1 \ ·} η r. c n — -> η / 3 «L ‘v O r X ; / t 1535, 1500, 1444, , 1330, 1278 ,
«ύ X* * /
-H NM? (3 00 MHz, DMSO-dg! δ 10.93 (br s, 1H! , 5.03 (s, 1
7.95 (s , 2h; , 7.89 'd, IH), 7.80 (d, IH!, 5. ,01 (t. i w 1 —- * · r
3.37 ιd, 2 H' ;
MS (FD) m/e 425 (M+);
UV (EtDH) 440nm (6=1169), 264nm (6=14109 ) .
Anal. Calcd for C15H9FCN3OS2: C, 42.35; H,2.13; N,9.88. Found: C, 42.60; H, 2.33; N, 9.63.
Example 2,60
0 N- f (2-t.hiazclvl: amino) thicxcmethvl-DL-2-chlcrochenvlalanlne methvl ester
A solution of 1-[ (2-thiazolyl) thiocarbamoyl] imidazole (1.5 g, 7.1 mmol) and DL-2-chlorcphenylalanine methyl ester hydrochloride (1.78 g, 7.1 mmol) in .V..V25 dimethylformamide (65 mL) was heated at 80°C for 7 h. The reaction was cooled to room temperature, the solvent removed under reduced pressure, and the residue recrystallized from ethyl ether-hexanes to provide 230 mg (12%; cf the titled product:
NM? (300 MHz, DMSO-dg) δ 7.38 (m, 3H) , 7.23 (m, 2H) , 7.08
AP/P/ 95 / 00723
BAD ORIGINAL
AP 0 0 0 3 8 8
-211(br s, 1H), 5.17 (q, 1H), 3.62 (s, 3H) , 3.21 (m, 2H);
MS (FD) m/e 355 (M+).
Example 261
Ν-I(2-thiazolvl)amine Ithicxomethvl-DL-4-chlorcphenvlalanine methvl ester
A solution of 1-[(2-thiazolyl) thiocarbamoyl] imidazole (1.5 g, 7.1 mmol) and DL-4-chlorophenylalanine methyl ester hydrochloride (1.78 g, 7.1 mmol) in N,Ndimethvlformamide (65 mL) was heated at 80’C fcr 6 h. The reaction was cooled to room temperature, the solvent removed under reduced pressure, and the residue recrystallized from ethyl ether-hexanes to provide 840 mg (20%) of the titled product:
IR (KBr, cm-1 ) 3176, 3025, 1735, 1562, 1510, 1493, 1467, 1452, 13c7, 1353, 1306, 1202, 1191;
!h NMR (3C0 MHz, DMSC-dg) δ 11.81 (br s, 1H) , 7.39 (m, 3H) ,
7.26 id, 2H), 7.18 (br s, 1H), 5.09 (q, 1H), 3.64 is, 3H), 3.18 (m, 2H) ;
MS (FD) m/e 355(M+);
UV (EtOH) 291nm (£=18545), 255 nm (£=11222), 220nm (£=16171), 201 (£=18545) .
Anal. Calcd for C12K14CIN3O2S2: C, 47.25; H, 3.96; N,
11.81. Found: C, 47.28; H, 3.94; N, 11.88.
Example 262
DL-3-(2-thiazclvl)-5-((4-chloro’phenvlmethvll-2-thicxo-4imi.dazQlidinaDg
A solution of N-[(2-thiazolyl)amino]thioxcmethylDL-4-chlorophenylalanine methyl ester (0.84 g, 2.36 mmol) and p-toluene sulfonic acid hydrate (0.20 g, 1.05 mmol) in
AP/P/ 9 5 / 0 0 7 2 3
BAD ORIGINAL
AP Ο Ο Ο 3 8 8
-212toluene '100 mL? was refluxed with a Dean-Stark trap for 4sh. The reaction was cooled to room temperature, the solvent removed under reduced pressure, residue taken up in ethyl acetate, washed with saturated sodium bicarbonate and saturated sodium chloride, dried ever magnesium sulfate, and concentrated under reduced pressure. The resulting product was recrystalli2ed from ethyl acetate-hexanes to provide 176 mg '23%) cf the titled product:
:Κ NMR (2 00 MHz, DMSO-dg) δ 7.83 !d, IH) , 7.78 (d, IH) , 7.38 10 ;d, 2H), 7.22 id, 2H), 4.85 it, IH), 3.11 (d, 2H) ;
MS (FD) m/e 323 :M+).
2¾ Apple-2,£2
N-ol-H-Jih-iazolyl) amlnolthloxomethyl-DL-415 trif luoromethy Iphen-ylalanlne methvl ester
A solution of 1-[(2-thiazolyl) thiocarbamoyl] imidazole (1.03 g, 4.1 mmol) and DL-4trifluoromethyIphenylalanine methyl ester hydrochloride (1.15 g, 4.1 mmol) in N, A’-dimethylformamide (75 mL) was heated at 80'C for 6 h. The reaction was cooled to room temperature, the solvent removed under reduced pressure, and tne residue recrystalli provide 389 mg '24%) of the
IR !K3r , cm’1 ) 3178, 3020
2 5 1185;
1 -K I.KR (300 MHz, DMSO-dg) ί
IH) , 7. 63 id, Σ.Κ), 7.39 (
IH) , 5. 18 fq, IK), 3.62 (s
MS (FD! m/e 385 (M+);
30 UV (EtOH) 291nm (£=18127),
:ed from ethyl ether-hexanes to titled product:
1747, 1577, 1509, 1325, 1278,
11.82 (br s, IH) , 9.82 (br s, 2H), 7.35 (d, IH), 7.13 (s,
3H), 3.31 (m, 2H);
nm (£=10867), 201nm (£=20712).
AP/P/ 9 5 / 0 0 7 2 3
BAD ORIGINAL
AP Ο Ο Ο 3 8 8
-213Anal. Calcd for C15H14N3F3O2S2: C, 46.26; H, 3.62; N,
10.79. Found: C, 46.21; H, 3.69; N, 11.00.
Example 264
DL-3- (2-thiazolvl) -5-J.i 4-trif luoromethyl) phenvlmethvl 1 -2thicx.o-4-.imidazolidinone
A solution of N-((2-thiazolyl) amino]thioxomethylDL-4-trifluoromethylphenylalanine methyl ester (0.34 g,
0.87 mmol) and p-toluene sulfonic acid hydrate (0.20 g
0.106 nmol) in toluene (100 mL) was refluxed with a DeanStark trap for 48 h. The reaction was cooled to room temperature, the solvent removed under reduced pressure, and the residue taken up in ethyl acetate, washed with saturated sodium bicarbonate and saturated sodium chloride, dried over magnesium sulfate, concentrated under reduced pressure to provide 145 mg (46%) of the titled product.
TR 'KBr, cm1) 3176, 1779, 1619, 1532, 1508, 1432, 1327, 1270, 1194, 1129;
ςΗ NMR (300 MHZ, DMSO-dg) δ 10.90 (br s, IH) , 7.83 (d, IH) ,
7.79 (d, IH), 7.65 (d, 2H), 7.41 (d, 2H) , 4.68 (t, IH),
3.22 (d, 2H) ;
MS (FD) m/e 357(M+);
IT/ (EtOH) 264nm (£=15626), 201nm (£=16341) .
Anal. Calcd for Οΐ4Ηιο?3Ν3θ52: C, 47.05; H, 2.82; N,11.76.
Found: C, 47.17; H, 2.82; N, 11.53.
Example ..265
N-f(2-thiazolvl) amino]thioxomethvl-DL-2.6difluorophenvlalanine methvl ester
A solution of 1-((2-thiazolyl) thiocarbamoyl] imidazole (0.65 g, 3.08 mmol) and DL-2,6AP/P/ 9 5 / 0 0 7 2 3
AP Ο Ο Ο 3 8 8
-214difluorophenylalanine methyl ester hydrochloride (0.78 g, 3.08 mmol) in A’,W-dimethylformamide (75 mL) was heated at 60 C for 7 h. The reaction was cooled to room temperature, the solvent removed under reduced pressure, and the residue recrystallized from ethyl ether-hexanes to provide 413 mg (38%) of the titled product:
IR (KBr, cm-1) 3205, 3036, 1737, 1625, 1554, 1511, 1468, 1442, 1388, 1265;
*H NMR (300 MHz, DMSC-dg) 5 11.83 'br s, OH), 7.37 'q, 2K) ,
7.08 (m, 2H), 5.21 (q, IH!, 3.62 ;s, 3H), 3.31 (m, 2H);
MS (FD) m/e 357(M*);
UV (EtOH) 291nm (£=18495), 256 nm (£=10695), 202nm (£=20082). Anal. Calcd for C14H13F2N3C2S2: C, 47.05; H, 3.67; N,
11.76. Found: C, 47.08; H, 3.76; N, 11.93.
Examplg .26.$
NrJ2^11mcygi.ohexenvl) ethvl 1-N1 -f 4,5,6.7 Lgir^frydrobenzothiazclvll thiourea
A solution of 2-(1-cyclohexenyl) ethyl isothiocyanate (1.67 g, 10 mmol) and 2-amino-4,5,6,7tetrahydrobenzothiazole (1.54 g, 10 mmol) in N,Ndimethylformamide (100 mL) was heated at 100’C for 120 h.
The reaction was coded to room temperature, the solvent removed under reduced pressure, the residue taken up in ethyl acetate and washed with IN HCl. The organic layer was concentrated and the residue recrystallized from ethyl acetate-hexanes to provide 426 mg (13 %) of the titled product:
AP/P/ 9 5/ 0 0 7 2 3
r .
AP Ο Ο Ο 3 β 8
-215IR (KBr, cm'1) 3169, 3031, 2931, 1580, 1258, 1198 ;
NMR (300 MHz, DMSO-dg) 6 11.41 (br s, IH) , 10.05 (br s,
IH), 5.43 (s, IH), 3.58 (m, 2H), 2.6-1.9 (m, 10H), 1.7 (m, 4H), 1.5 (m, 4H) ;
MS (FD) m/e 321 (M*);
TJV (EtOH) 298nm (£=12157) , 257nm (£=6569) , 201nm (£=12172) . Anal. Calcd for Ci£H23N3S2: C, 59.97 H, 7.21; N, 13.07. Found: C, 60.06; H, 6.95; N, 12.82.
Example 267
N-(2-(1-cvdohexe nyDethvl1-Ν' -f2-(5-chloro-pyrazinyl) thiourea
A solution of 2-(1-cyclohexenyl)ethyl
isothiocyanate (2.30 g, 13.7 mmol) and 2-amino-5-
15 chloropyrazine (1.75 g, 13.7 mmol) in N, //-dimethyl formamide
(40 mL) was heated at 100'C for 192 h. The reaction was coded to room temperature, the solvent removed under reduced pressure, and the residue taken up in ethyl acetate and washed with IN aqueous HCl. The organic layer was concentrated and the resulting product was recrystallized from ethyl acetate-hexanes to provide 64 mg (1.6%) of the titled product:
IR (KBr, cm'1) 3192, 2931, 1588, 1515, 1457, 1320, 1251, 1153;
-H NMR (300 MHz, DMSO-dg) δ 11.01 (br s, IH) , 10.45 (t, IK',
8.38 (d, IH), 8.29 (d, IH) , 5.50 (br s, IH) , 3.63 (q, 2H), 2.21 (t, 2H), 1.95 (m, 4H), 1.52 (m, 4H);
MS (FD) m/e 296 (M+);
UV (EtOH) 330nm (£=9176) , 273nm (£=21432 ) , 201nm (£=10972 ) .
AP/P/ 95/00723
APO Ο Ο 3 8 8
-216Anal. Calcd for O13H17N4SCI: C, 67.28; H, 8.30; N, 13.85. Found: C, 67.55: H, 8.48; N, 13.54.
Ey ample .2 ¢3
N-J2 -_(1 -cv.cloh.exeny.il ethvl!-Ν'-(2-(4-(3,4dicr.lorephezYl’-lihlszQlylJ , thiourea
A solution of 2-'1-cyclohexenyl ] ethyl isothiocyanate '1.67 g, 10 mmol) and 4-(3,4dichlcrophenyl)-2-thiazoiamine (2.45 g, 10 mmol) in Ν,ΧΙΟ dimethylformamide (50 mL' was heated at 100’C for 120 h.
The reaction was cooled to room temperature, the solvent removed under reduced pressure, and the residue taken up in ethyl acetate and washed with IN HCl. The organic layer was concentrated and the residue recrystallized from ethyl acetate-hexanes to provide 533 mg (2.3%) of the titled product:
IP. (KSr, cm'1) 3169, 2927, 1573, 1558, 1523, 1460, 1393, 1295, 1214 ;
7 ,, NMR (300 MHZ, DMSO-dg ) δ 11.72 (br s. IH), 9.11 (br s,
20 IH) , 8.07 (d, IE), 7.83 (m. IH), 7.62 (m, , 2H), 5.45 (m,
IH) , 3.60 (m, 2-', 2.21 (m, 2H), 1.85 (m, , 4H), 1.43 (m,
4H)
MS (FD) m/e 411 Ή+) ;
17/ (MeOH) 287nm (£=25040) -5 / 41nm (£=16142) , 2C5nm (£=29362) .
25 Ana 1. Calcd for OI8K19N3S2C. 12: C, 52. 42; H, 4.64; N, 10.19
AP/P/ 9 5 / 0 0 7 2 3
Found: C, 52.63; H, 4.48; N, 10.21.
Example, £9.
1- (2-f2-methoxvphenvllethyl) thiocarbamovl imidazole 30 A solution of 1,1'-thiocarbonyldiimidazole (1.78 g, 10 mmol) and 2-methoxyphenethylamine (1.51 g, 10 mmol)
BAD ORIGINAL
ΑΡ υ υ υ ο 8 8
-217in acetonitrile (25 mL) was stirred at room temperature for 20 h. The resulting precipitate was collected by filtration to provide 1.40 g (53%) of the titled product:
IR (KBr, cm-1) 2544, 1563, 1493, 1409, 12S2, 1246, 1031,
755;
NMR (300 MHz, DMSO-cf6) δ 12.0 (br s, IH) , 7.65 (S, IH) , 7.25 (nV, 2H), 7.05-6.9 (m, 4H), 3.8 (m, 2H), 3.8 <s, 3H) , 2.95 (t, J=7 Hz, 2H);
MS (FD) m/e 261 (M+) ;
UV (EtOH) 278nm (£=7083), 216 nm. (£=12633), 203 nm (£=22221).
Exarcple 27Q
Ν-·2-(2-methoxvphenvl)ethvll-Ν' -(2-cvridvl? thiourea
A solution of 1-(2-(215 methoxyphenyl]ethyl)thiocarbamoyl imidazole (0.52 g, 2 mmol) and 2-aminopyridine (0.19 g, 2 mmol) in Ν,Νdimethylformamide (5 mL) was stirred at 90‘C for 4 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 0.25 g (44%) of the titled product: IR (KBr, cm1) 3219, 3048, 1607, 1557, 1236, 1036, 756;
!h NMR (300 MHz, DMSO-dg) δ 11.65 (m, IH) , 10.55 (br s, IK), 8.1 (m, IH), 7.75 (m, IH), 7.3-6.9 tin, 6H), 3.8 tin, 2H),
3.78 (s, 3H), 2.9 (t, J=7 Hz, 2H);
MS (FD) m/e 287 (M*); UV (EtOH) 290nm (£=10141), 267nm (£=13121), 247 nm (£=10959), 202 nm (£=24078).
AP/P/ 9 5 / 0 0 7 2 3
AP Ο Ο Ο 3 8 8
-218Ν- f 2-11.-cyclohexeny 12ethyl 1 -Η' - Γ2- (6-methyl)pyridvll thiourea
A solution of 2 - (1-cyclohexenyl) ethyl 5 isothiocyanate (1.67 g, 10.0 mmol) and 2-amino-6methylpyridine (1.08 g, 10.0 mmol) in N, N-dimethylformamide (25 mL) was heated at 90C for 20 h. The reaction was cooled to room temperature and the solvent removed under reduced pressure. The resulting product was recrystallized from ethyl acetate-hexanes to provide 1.04 g (38%) of the titled product:
ZR (K3r, cm-1) 3230, 2920, 1608, 1572, 1540, 1457, 1378, 1317, 1235, 1164;
3H NMR ¢300 MHz, DMSC-dg) δ 11.7 (br t, IH) , 10.45 is, IH) , 15 .62 (t, IH), 6.95 (d, IH), 6.90 (d, IH), 5.50 (br s, IH),
3.7 (q, 2K), 2.4 (s, 3H), 2.25 (t, 2H) , 1.95 (m, 4H), 1.55 im, 4H);
MS (FD) m/e 275 (M+);
UV (ZtOH) 296nm (£=17669), 265nm (£=16667), 247nm (£=15266).
Anal. Calcd for C15K21N3S: C, 65.42; H, 7.69; N, 15.26.
Found: C, 65.42; H, 7.75; N, 15.20.
N- F2- ΐ 1-cyclohexenyl^ ethvll -N‘ - f 2 - (5-methyl) pyridyl 1 25 thiourea
A solution of 2- (1-cyclohexenyl) ethyl isothiocyanate (1.67 g, 10.0 mmol) and 2-amino-5methylpyridine (1.08 g, 10.0 mmol) in N, N-dimethylformamide (25 mL) was heated at 90‘C for 20 h. The reaction was cooled to room temperature and the solvent removed under reduced pressure. The resulting product was recrystallized
AP/P/ 95/00723
BAD ORIGINAL &
AP Ο Ο Ο 3 8 8
-219-
from ethyl acetate-hexanes to provide 1.06 g (39%) of the
titled product: IR irSr, cm1) 3225, 2933, 1596, 1569, 1532, 1494, 1344,
5 1311, 1232, 827; -H KMR (300 MHz, DMSO-dg) δ 11.55 (br t, IH), 10.45 (s, IK)
7.95 'br s, IH), 7.6 (dd, IH), 7.05 (d, IH), 5.5 (br s, IH), 3.7 ,'q, 2H) , 2.3 (m, 5H> , 1.95 (m, 4H) , 1.55 (m, 4H) ; MS (FO) m'e 275 (M+) ;
UV (EtOH) 22Snm (£=13663) , 268nm (£=21631) , 249nm (£=14893 ) . Anal. Calcd for C15H21N3S: C, 65.42; H, 7.69; N, 15.26. Found: C, 65.15; H, 7.75; N, 15.33.
Example
222
N- :2- (1-cvclohexenvl?ethvll -N‘-,f 2-(4-methvl )pvridvl) ihiourea
A solution of 2-(1-cyclohexenyl) ethyl isothiocyanate (1.67 g, 10.0 mmol) and 2-amino-4methylpvridine (1.08 g, 10.0 mmol) in N, N-dimethylformamide (25 mL) was heated at 90*C for 16 h. The reaction was cooled to room-temperature and the solvent removed under reduced pressure. The resulting product was purified by HPLC to provide 1.67 g (61%) of the titled product;
-R (E~r, cm1) 3220, 2935, 1617, 1535, 1487, 1322, 1188,
66 ;
-H TOCR -.300 MHz, DMSO-dg) δ 11.65 (br t, IH) , 10.45 (s, IH) , S.O (d, IH), 6.95 (s, IH), 6.85 (d, IH), 5.5 (br s, IH), 3.65 (q, 2H), 2.3 (m, 5H), 1.95 (m, 4H), 1.55 'm, 4H);
MS (FD) m/e 275 (M+);
UV (EtCH) 2£?nm (£=16865) , 266nm (£=17870! , 247nm (£=14179 ) , £ Z L 0 0 / 5 6 /d/dV
202nm (£=20105).
BAD ORIGINAL $
AP ο ο Ο 3 8 8
-220Anal. Calcd for C15H21N3S: C, 65.42; H, 7.69; N, 15.26. Found: C, 65.16; H, 7.55; N, 15.30.
Example. 274
N-f 2-(..l-cyclohexenvl) ethvl I-N* - f2- (3-methyl)pvridvl1 thiourea
A solution of 2-(1-cyclohexenyl)ethyl isothiocyanate (1.67 g, 10.0 mmol) and 2-amino-3methy ipyridine (1.08 g, 10.0 mmol) in N, N-dimethylformamide <25 mL) was heated at 90’C for 16 h. The reaction was cooled to room temperature and the solvent removed under reduced pressure. The resulting product was purified by HPLC to provide 1.8 g (65%) of the titled product;
IR (K3r, cm-1) 3220, 2931, 1589, 1513, 1462, 1325, 1164;
-H NMR (300 MHz, DMSO-dg) δ 11.6 (br t, IH) , 8.65 (s, IH) ,
8.05 (d, IH), 7.65 (d, IH), 7.05 (dd, IH), 5.5 (br s, IH), 3.65 (q, 2H), 2.3 (s, 3H), 2.25 (t, 2H) , 1.95 (m, 4H), 1.55 (m, 4H);
MS (FD) m/e 275 (M+);
UV (EtOH) 293nm (£=16693), 264nm (£=14464), 244nm (£=14762), 201nm (£=16723) .
Example 275
Κ-Γ2-(1-cvclohexenvl)ethyl)-Ν'-f2-(6-ethyl)pvridvl 1 thiourea
A solution of 2-(1-cyclohexenyl)ethyl isothiocyanate (1.67 g, 10.0 mmol) and 2-amino-6ethylpyridine (1.22 g, 10.0 mmol) in N, N-dimethyl f ormamide (25 mL) was heated at 90'C for 20 h. The reaction was cooled to room temperature and the solvent removed under
AP/P/ 9 5 / 0 0 7 2 3
BAD ORIGINAL r~~
AP Ο Ο Ο 3 8 8
-221reduced pressure. The resulting product was purified hy HPLC to provide 1.55 g (54%) of the titled product;
IR (KBr, cm’1) 3230, 2930, 1604, 1533, 1450, 1211, 1157;
1H NMR (300 MHz, DMSC-dg! δ 11.8 (br t, IH! , 10.45 (s, IH),
7.62 (t, IH), 6.95 id, IH), 6.90 (d, IH), 5.45 (br s, IH) ,
3.7 (q, 2H), 2.7 (q, 2H), 2.25 it, 2H!, 1.95 im, 4H), 1.55 (m, 4H), 1.2 it, 3H);
MS (FD) m/e 289 (M*) ;
UV (EtCH) 296nm (£=17903) , 265nm (£=16556' , 247nm (£=14932) , 10 201nm (£=14174) .
Anal. Calcd for C16H23N3S: C, 66.40; H, S.C1; N, 14.52. Found: C, 66.40; H, 8.0C; N, 14.75.
Example 2~6
Ν-Γ2- il-cvclchexenvlJethvl 1 -N* - (2- 4-ethvl)pyridvll isisursa
A solution of 2-(1-cyclohexenyl}ethyl isothiocyanate (1.67 g, 10.0 mmol) and 2-amino-4ethylpyridine (1.22 g, 10.0 mmol) in N, N-dimethyl form, amide (25 mL) was heated at 90’C for 16 h. The reaction was cooled to room temperature and the solvent removed under reduced pressure. The resulting product was purified by HPLC to provide 1.2 g (42%) of the titled product;
IR (KBr, cm’1) 3215, 2931, 1615, 1535, 1407, 1334, 1198,
843;
1H NMR (300 MHz, DMSO-dg) δ 11.68 (br t, IH) , 10.45 (s, IH) , 8.0 (d, IH), 7.0 (s, IH) , 6.9 (d, IH), 5.5 (br s, IH) , 3.65 (q, 2H), 2.6 (q, 2H>, 2.25 it, 2H), 1.95 (m, 4H), 1.55 (m, 4H), 1.15 it, 3H);
AP/P,· 9 5/ 0 0 7 2 3
AP Ο Ο Ο 3 8 8
-222UV (EtOH! 285nm (£=173^8), 266nm (£=18654), 247nm (£=14847), 202nm (£=23101) .
Anal. Calcd for C16K23N3S: C, 66.40; H, 8.01; N, 14.52. Found: C, 66.45; H, 7.99; N, 14.26.
Example 2 2
NrJ-2-- d--Cvdphsxer,yd ethyl ]-Ν·-Γ2-!5triflusrpr.ethyl; pyridyl! thiourea A solution cf 2- (1-cyclohexenyl'ethyl isothiocyanate (1.67 g, 10.0 mmol) and 2-amino-5trifluorcmethylpyridine (1.62 g, 10.0 mmol) ir. N,Ndimethylformamide (25 mL) was heated at 90*C for 72 h. The reaction was coded to room temperature and the solvent removed under reduced pressure. The resulting product was purified by HPLC to provide 0.33 g (10%) of the titled product ,IR (KBr, cm“l) 3220, 2929, 1618, 1551, 1500, 1324, 1238, 1132, 1078, 828;
Ih NMR (300 MHz, DMSO-c?g) δ 11.4 (br t, IH) , 1C.95 (s, IH) ,
8.5 (br s, IH), 8.15 (dd, IH), 7.3 (d, IH), 5.55 (br s,
IH), 3.7 (q, 2H), 2.3 (t, 2H), 1.95 !m, 4H), 1.55 (m, 4H) ; MS (FD) m/e 329 (M+);
UV (EtOH) 296nm (£=17058) , 255nm (£=14250) .
Anal. Calcd for C15H18N3F3S: C, 54.70; H, 5.51; N, 12.76.
Found: C, 54.98; H, 5.67; N, 12.59.
AP/P/ 9 5 / 0 0 7 2 3
AP Ο Ο Ο 3 8 8
-223Example 278
Nr. 12-.7-1cvclohsxanynethvl) rH,.-I2--i4-methvl) thiazolvll thiourea
A solution of 1-t(2-[4-methyl]thiazolyl) thiocarbamoyi] imidazole (1.0 g, 4.46 mmol) and 2cyclohexanylethylamine (0.567 g, 4.46 mmol) in Ν,Νdimethylformamide (25 mL) was stirred at 90'C for 16 h, the reaction was coded to room temperature and the solvent removed' in vacuo. The residue was crystallized from ethyl acetate to provide 0.72 g (57%) of the titled product:
IR (KBr, cm'1) 3220, 2922, 1565, 1505, 1227, 1168;
1K NMR (300 MHz, DMSO-C?g) δ 11.5 (br s, IH) , 9.9 (br s, IH) , 6.65 (s, IH), 3.55 (m, 2H), 2.25 (s, 3H), 1.8-0.8 (m, 13H) ; MS (FD) m/e 283 (M+);
UV (EtOH) 291nm (6=5315) , 257nm (6=2711) .
Anal. Calcd for C13H21N3S2: C, 55.09 H, 7.47,- N, 14.82. Found: C, 55.29; H, 7.60; N, 14.64.
Example 279
N-f.2-(2-methoxvphenvl) ethyl]-Ν' -Γ2-(5-methyl)pvridvl1 thiourea
A solution of 1-(2-(2methcxyphenyl]ethyl)thiocarbamoyi imidazole (0.7 g, 2.68 mmol) and 2-amino-5-methylpyridine (0.29 g, 2.68 mmol) in
N, N-dimethyl formamide (5 mL) was stirred at 90*C for 16 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 0.62 g (77%) of the titled product:
IR (K3r, cm'1) 3227, 2932, 1612, 1534, 1493, 1273, 1037;
^•H NMR (300 MHZ, DMSO-dg) δ 11.55 (br t, IH) , 10.45 (s, IH) ,
K3 eu co co on £
£ <
BAD ORIGINAL Ά
AP Ο Ο Ο 3 8 8
-2247.9 (br s, IH), 7.6 (m, 1H), 7.2-6.9 (m, 5H>, 3.8 (m, 5H) ,
2.9 (t, J=7 Hz, 2H), 2.2 (S, 3H) ;
MS (FAB) m/e 302 (M+H);
UV (EtOH) 298nm (£=13316), 268nm (£=23132), 249 nm (£=15574), 5 202 nm (£=25460) .
Anal. Calcd for Ci6Hi9N3OS: C, 63.76; H, 6.35; N, 13.34. Found: C, 63.71; H, 6.34; N, 13.79.
.-.Γ2-(2· ) ethyl I-thiocarbamoyl imidazole
A solution of 1,1’-thiocarbonyldiimidazole (1.8 g, 10 mmol) and 2-(2-chlorophenyl)ethyl amine (1.55 g, 10 mmol) in acetonitrile (100 mL) was stirred at room temperature for 3 h. The solution was concentrated to about 50 ml and was placed in the freezer for 4 days. The resulting crystals were collected by filtration to provide 2.37 g (89%) of crude title product.
mp 7 4 - 7 8 ’ C.
IR (KBr, cm'1) 3134, 2924, 1564, 1529, 1474, 1448, 1411, 1353, 1287, 1215;
MS (FD) m/e 266 (M+);
UV (EtOH) 278nm (£=5421), 247 nm (£=5655), 202 nm (£=22240).
AP/P/ 9 3/ 0 0 7 23
Example 2S1
N-f2-(2-chlorophenvl'ethvll-Ν' -f2-fS-methvl'pvridvl1 thiourea
A solution of 1-(2-(2chlorophenyl]ethyl)thiocarbamoyl imidazole (1.0 g, 3.76 mmol) and 2-amino-5-methylpyridine (0.41 g, 3.76 mmol) in
N,N-dimethylformamide (10 mL) was stirred at 90 C for 16 h,
BAD ORIGINAL
AP Ο Ο Ο 3 8 8
-225the reaction was coded to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 0.92 g (80%) of the titled product:
IR (KBr, cm'1) 3226, 1597, 1532, 1491, 1273, 1050;
1H NMR (300 MHz, DMSO-d$) δ 11.6 (br t, IH) , 10.5 (s, IH),
7.9 (br s, IH), 7.6-7.0 (m, 6H), 3.9 (q, 2H), 3.1 (t, J=7 Hz, 2H), 2.2 (s, 3H);
MS (FD) m/e 305 (M*);
UV (EtOH) 2S8nm (£=14145), 268nm (£=21034), 249 nm (£=15757), 10 202 nm (£=23053) .
Anal. Calcd for C15H15N3CIS: C, 58.91; H, 5.27; N, 13.74. Found: C, 58.65; H, 5.39; N, 13.77.
l-f(2-(4-ethvl)thiazolyl)thiocarbamoylI imidazole
A solution of 1,1'-thiocarbonyldiimidazole (11.9 g, 60 mmol) and 2-amino(4-ethyl)thiazole (8.0 g, 60 mmol) in acetonitrile (250 mL) was stirred at room temperature for about 5 h. The resulting precipitate was collected by filtration to provide 12.0 g (85%) of the titled product, mp. 198-200‘C; IR (KBr, cm'1) 2970, 2637, 1609, 1529,
1461, 1398, 1357, 1226, 1262;
IH NMR (300 MHz, DMSO-dg) δ 8.6 (s, IH) , 7.9 (s, IH) , 7.0 (s, IH), 6.9 (s, IH), 2.6 (q, J=7 Hz, 2H), 1.2 (t, J=7 Hz,
3H);
MS (FD) m/e 238 (M+);
UV (EtOH) 361 nm (£=11223), 290 nm (£=8828), 203 nm (£=20303) .
Anal. Calcd for C9H10N4S2: C, 45.36 H, 4.23; N, 23.51.
Found: C, 45.51; H, 4.20; N, 23.53.
ho oc
If)
5.
CL <
BAD ORIGINAL 4
APO 0 0 3 8 8
-226Exasple 283.
Ν-.ί2-,12-ρνχίάν11βΐ;Ην1) -Ν' -.12- (4-ethvK thiazolvll thiourea
A solution of 1-((2-(4ethyl]thiazolyl)thiocarbamoyl] imidazole (1.00 g, 4.2 mmol) 5 and 2-(2-aminoethyl)pyridine (0.51 g, 4.2 mmol) in Ν,Νdimethylformamide (25 mL) was stirred at 90‘C for 3 h, the reaction was cooled to rocm temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 0.75 g (61%) of the titled product:
IR (KBr, cm-1) 3163, 1557, 1524, 1222, 757;
!h NMR (300 MHz, DMSO-dg) δ 11.3 (br s, IH), 10.0 (br s,
IH), 8.5 (m, IH), 7.7 (m, IH), 7.25 (m, 2H), 6.6 (s, IH),
3.9 (m, 2H), 3.05 (m, 2H), 2.45 (q, J=7 Hz, 2H), 1.05 ;t, J=7 Hz, 3H); MS (FD) m/e 252 (M+);
UV (EtOH) 292nm (€=17803), 261nm (€=12919), 201 nm. (€=17809). Anal. Calcd for C13H16N4S2: C, 53.40 H, 5.51; N, 19.16. Found: C, 53.64; H, 5.51; N, 19.02.
Example 284
N-(2-fl-cvclohexenvl]ethyl)-Ν' -(2-(4 - ethyl)thiazolyl] thiourea
A solution of 1-((2-[4-ethyl]thiazolyl) thiocarbamoyl] imidazole (0.75 g, 3.15 mmol) and 2-(1cyclohexenyl)ethylamine (0.39 g, 3.15 mmol) in N,N25 dimethyl formamide (15 mL) was stirred at 90*C for 4 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 0.77g (83%) of the titled product:
MP 155-156‘C; IR (KBr, cm1) 3172, 2914, 1560, 1507, 1202,
710;
AP/P/ S 5 / 0 0 7 2 3
AP Ο Ο Ο 3 8 8
-227ΧΗ NMR {300 MHz, DMSO-dg) δ 11.5 (br s, IH), 9.8 (br s, IH) , 6.6 (s, IH), 5.42 (s, IH), 3.56 (q, J=7 Hz, 2H), 2.45 tin,
2H), 2.16 tin, 2H), 1.9 (m, 4H), 1.5 tin, 4H), 1.12 (t, J=7 Hz, 3H) ;
MS (FD) m/e 295 (M+);
UV (EtCH) 291nm (£=19227), 257nm (£=9628), 201 nm (£=15736). Anal. Calcd for C14H21N3S2: C, 56.91 H, 7.16; N, 14.22. Found: C, 57.20; H, 7.22; N, 14.16.
Example ,.285
N-F2-(2-chlorophenvl)ethvl)-Ν'-f2-U-ethvl)thiazolyll.
phipurea
A solution of 1-[(2-[4-ethyl]thiazolyl) thiocarbamoyl] imidazole (0.75 g, 3.15 mmol) and 2-(2chlorophenyl)ethylamine (0.49 g, 3.15 mmol) in N,N~ dimethylformamide (15 mL) was stirred at 90'C for 2 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 0.85 g (83%) of the titled product:
MP 153-155’C; IR (KBr, cm’1) 3167, 3018, 1570, 1505, 1215, 749, 699;
2H NMR (300 MHz, DMSO-dg) δ 11.65 (br s, IH) , 9.85 (br s,
IH), 7.5-7.2 (m, 4H), 6.65 (s, IH), 3.85 (m, 2H), 3.05 (t,
J = 7 Hz, 2H), 2.55 (q, J=7 Hz, 2H) , 1.1 (tc, J=7 Hz, 3H) ;
MS (FD) m/e 325 (M+);
UV (EtOH) 292nm (£=19154), 257nm (£=10451), 202 nm (£=24308). Anal. Calcd for Ci4HigN3S2Cl: C, 51.60; H, 4.95; N, 12.87. Found: C, 51.75; H, 4.98; N, 12.79.
£ z L 0 0 / C 6 zd/dv bad original
AP Ο Ο Ο ό 8 8
-228Examc-e2S5
Ν- ί2- 12-r.£thhx\’Dhenvl) ethvlL-Nti-JiL· 14_-gthy.l) thiazolyl I thiourea
A solution of 1-((2-[4-ethyl]thiazolyl) thiocarbamoyl) imidazole (0.70 g, 2.94 mmol) and 2-(2methoxyphenyi: ethylamine (0.44 g, 2.94 mmol) in n,ndimethylformamide (15 mL) was stirred at 95'C for 2 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 0.67 g (71%) of the titled product:
MP 166-167.5’C; IR (KBr, cm-1) 3173, 3025, 1528, 1248,
1209, 755, 677;
NMR (300 MHz, DMSO-dg) 5 11.5 (br s, IH) , 9.85 (br s,
IH) , 7.2-6.8 tin, 4K) , 6.57 (s, IH), 3.7 (m, 5H), 2.82 (t,
J=7 Hz, 2H) , 2.4 (q, J=7 Hz, 2H) , 1.06 (t, J=7 Hz, 3H) ;
MS (FD) m/e 321 (M+);
UV (EtOH) 291na (£=12114), 259nm (£=6792) Γ 201 nm (£=18914). Anal. Calcd for C15H19N3OS2: C, 56.04; H, 5.96; N, 13.07. Found: C, 55.83; H, 6.00; N, 13.08.
Example 287
Ν- Γ2- (3-methoxyphenyl)ethyl] -N1 - 12- (4-ethvl) thiazolyl) .thiourea
A solution of 1-((2-[4-ethyl]thiazolyl) thiocarbamoyl] imidazole (0.70 g, 2.94 mmol) and 2-(3methoxyphenyl)ethylamine (0.44 g, 2.94 mmol) in Ν,Νdimethylformamide (15 mL) was stirred at 90‘C for 2 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 0.76 g (80%) of the titled product:
MP 123-125‘C;
AP/P/ 9 5 / 0 0 7 2 3
BAD ORIGINAL
APO 0 0 3 8β
-229IR (KBr, cm*1) 3167, 3027, 1587, 1207, 699;
^H NMR (300 MHz, DMSO-dg) δ 11.5 (br s, IH) , 9.9 (br s, IK), 7.2-6.8 (m, 4H), 6.58 (s, IH), 3.75 (m, 2H), 3.67 (s, 3H),
2.84 (t, J=7 Hz, Hz, 3H);
2H)
2.45 (q, J=7 Kz, 2H), 1.05 (t, J=7
MS (FD) m/e 321 (M*);
UV (EtOH) 292nm (£=19113), 258nm (£=10607), 202 nm (£=29289). Anal. Calcd for C15H19N3OS2: C, 56.04; H, 5.96; N, 13.07.
Found: C, 56.08; H, 5.96; N, 13.16.
Example.. 282
1-j (2-.14--cyano J thiazolvl) thiocarbamoyn imidazole
A solution of 1,1'-thiocarbonyldiimidazole (3.2 g, 16 mmol) and 2-amino-4-cyanothiazole (2.0 g, 16 mmol) in acetonitrile (40 mL) was stirred at room temperature for 72 h and heated at 6Q'C for 24 h. The resulting precipitate was collected by filtration to provide 2.74 g (73%) of the titled product:
IR (KBr, cm-1) 3097, 2230;
NMR (300 MHz, DMSO-d6) δ 11.99 (br s, IH) , 8.76 (s, IH) , 8.67 (s, IH) , 8.07 (s, IH) , 7.92 (s, IH) ;
MS (FAB) m/e 236 (M+H).
£ 7. L 0 0 / c 6 /d/dV
Examole 289
N-F2-!2-chlorochenvlJ ethyl1-N1 -(2-(4-cvano)thiazolvl) thiourea A solution of 1-((2-(4cyano]thiazolyl) thiocarbamoyl] imidazole (0.66 g, 2.8 mmol) and 2-(2-chlorophenyl)ethylamine (0.45 g, 2.8 mmol) in N,Ndimethylformamide (15 mL) was stirred at 100'C for 2 h.
BAD ORIGINAL
AP Ο Ο Ο 3 8 8
-230The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCI, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue purified by chromatography on silica gel to provide 0.24 g (26%) of the titled product :
mp 165-168’C; IR (KBr, cm1) 3119, 2955, 2232, 1577, 1505, 1461, 1328, 1299, 1221, 1C53, 826;
^Η NMR (300 MHz, DMSO-dg) 5 11.8 'br s, IH) , 8.5 (br s, IH) ,
1C 8.1 (s, 1ΚΪ, 7.2-7.4 !m, 4H) , 3.74 (m, 2H), 2.98 (t, J=7
Hz, 2H);
MS (FD) rn/e 322 fM+);
UV (EtOH) 2S7nm (£=10082), 258 nm (£=15462), 2C5 nm (£=31601) .
Example 290
K-i2-i2_-chlProph.envlJ ethvl 1 -Ν' - (2- (4-cvano) thiazolvll
A solution of l-[(2-[420 cyano3thiazolyl>thiocarbamoyl] imidazole (0.66 g, 2.8 mmol) and 2-(3-chlorophenyl)ethylamine (0.44 g, 2.8 mmol) in N,Ndimethylformamide (15 mL) was stirred at 90'C for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCI, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from methylene chloride to provide 0.21 g (23%) of the titled product as a tan solid:
mp 180-185’C; IR (KBr, cm’1) 2955, 2239, 1559, 1522, 1331,
1251, 1206, 1168, 823;
AP/P/ 9 o / 0 0 7 2 3
BAD ORIGINAL s»
AP Ο Ο Ο 3 8 8
-231 3Η NMR (300 MHz , DMS0-d6> δ 11.8 (br s, 1Η), 8.4 (br s, IH), 8.1 (s, IH), 7.1-7.3 (m, 4H) , 3.71 (m, 2H), 2.86 (t, J=7 Hz, 2H);
MS (FD) m/e 322 (M4), 324;
UV (EtOH) 287nm (£=10684), 258 nm (£=16406), 207 nm (£=23113) .
Example 291
N-I2- (2-m.ethoxvp.henvl) ethvll -Ν' - i2- (4-cvano? thiazolyl)
-3 ihiourea
A solution of 1-((2-(4cyano]thiazolyl)thiocarbamoyl] imidazole (0.66 g, 2.8 mmol) and 2-(2-methcxyphenyliethylamine (0.46 g, 2.8 mmol) in N,N-dimethylformamide (15 mL) was stirred at 90*C for 2 h.
The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue purified by chromatography on silica gel to provide 0.21 g (23%) of the titled product as a yellow solid: mp 159-161C;
IR (KBr, cm-1) 2937, 2235, 1566, 1454, 1301, 1243, 1208,
1173, 754;
2H NMR (300 MHZ, DMSO-d6) δ 11.8 (br s, IH) , 8.4 (br s, IH),
8.1 (s, IH), 6.8-7.2 (m, 4H), 3.73 (s, 3H), 3.66 (m, 2H),
2.81 (t, J=7 Hz, 2H);
MS (FD) m/e 318 (M4);
UV (EtOH) 279nm (£=12102), 259 nm (£=16281), 203 nm (£=33347) .
AP/P/ 9 3/ 0 0 7 2 3
APO 0 0 3 8 8
-232Exarjle· 29.2
N- 1 f2-.ί3-methoxvτh£r.yl·;ePhyll-N, - f2- (4-cvar.oi,thiazolyn ££ig.ux.ea
A solution of 1-((2-(45 cyano]thiazolyl)thiocarbamovl] imidazole (0.66 g, 2.8 mmol) and 2-(3-methoxyphenyl)ethylamine (0.44 g, 2.8 mmol) in N, N-dimethylformamide (15 ml) was stirred at 90'C for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and trine. The organic layer was concentrated and the residue purified by chromatography on silica gel to provide 0.21 g (23%) of the titled product as a yellow solid:
mp 151-153'C;
IR (KBr, cm1) 3065, 2235, 1564, 1515, 1295, 1250, 1209,
1155, 1058, 874, 768, 748, 684;
NMR (3 00 MHz, DMSO-dg) δ 11.8 (br s, IH), 8.4 (br s, IH) , 8.1 (s, IH), 7.18 (m, IH), 6.77 (m, 3H), 3.68 (m, 5H) ,
2.80 (t, J=7 Hz, 2H);
MS (FD) m/e 318 (M*);
UV (EtOH) 280nm (£=11770), 258 nm (£=16613) , 204 nm (£=34785) .
Example 293
N-f 2-.( 1-cvclohexenvl' ethvl]-N1 - ί 2- /4cyar.o’·' thiazolyl] thiourea
A solution of 1-((2-(4cyano]thiazolyl)thiocarbamoyl] imidazole (0.82 g, 3.5 mmol) and 2-(1-cyclchexenyl)ethylamine (0.45 g, 3.5 mmol) in N,N30 dimethylformamide (15 mL) was stirred at 90'C for 1.5 h.
AP/P/ 93/007Z3
AP Ο Ο Ο 3 8 8
-233ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was purified by chromatography on silica gel to provide 0.27 g (26%) of the titled product as a pale yellow solid: mp 176-178‘C;
IR (KBr, cm’1) 3169, 3075, 2924, 2233, 1556, 1513, 1330, 1298, 1260, 1217, 1200, 1167, 1145, 983, 922;
NMR (30C MHz, DMSO-dg) 5 11.87 (br S, IH), 8.40 (tr s,
IH), 8.11 (s, IH), 5.42(br s, IH) , 3.52 (m, 2H) , 2.14 (t,
J=7 Hz, 2H), 1.90 (m, 4H), 1.49 (m, 4H);
MS (FD' m/e 292 (M+>;
UV (EtOH) 2SSnm (£=11250), 258 nm (£=16113), 206 nm (£=25473)
Anal. Calcd for C13H16N4S2: C, 53.40; H, 5.52; N, 19.16. Found: C, 53.10; H, 5.55; N, 18.96.
Example 294
Id (2-ί4r.13-chlorophenvl)thiazolyl)thiocarbamoyl] imidazola 20 A solution of 1,11-thiocarbonyldiimidazole (2.52g, 12 mmol) and 4-(3-chlorophenyl)-2-thiazoleamine (2.14 g, 12 mmol) in acetonitrile (35 mL, was stirred at room temperature for 30 hours. The resulting precipitate was collected by filtration to provide 2.77 g (72%) of the titled product:
AP/P/ 9 5 / 0 0 7 2 3
BAD ORIGINAL $
AP Ο Ο Ο 3 8 8
-234Μ-1.2.- i.2r.chlorcrhenvl: ethvll -Ν' -(2-f4-<3chlcrcchenyl’'thiazolyl thiourea
A solution of 1-/2-(4-(35 chi oropheny 1] thiazolyl ' thiocarbamoyl] imidazole (0.92 g,
2.86 mmol) and 2-(2-chlorophenyl)ethylamine (0.46 g, 2.86 mmol) in N,N-dimethylformamide (15 mL) was stirred at 90*C fcr 2 h. The reaction was coded to room temperature, poured into ethyl acetate, washed with water, IN acueous
HCl, w’ater, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from EtCAc to provide 1.0 g (86%) of the titled product as yellow needles:
mp 193-1S5*C;
CR (KBr, cm1) 3018, 1560, 1515, 1470, 1291, 1210, 1065,
935, 785, 757, 716;
I'H NMR (300 MHz, CMSC-dg) δ 11.66 (br s, IH) , 9.29 (br s, IH), 7.79 (s, IH), 7.63 (m, 2H), 7.35 (m, 4H), 7.23 (m,
2H), 3.83 (m, 2H), 3.02 (t, J=7 Hz, 2H) ;
MS (FD) m/e 407 (M+) , 409 (K-2);
UV (EtOH) 285nm (£=22709), 266 nm (£=20608), 202 nm (£=37861) .
Anal. Calcd for C18H3.5N3S2CI2: C, 52.94; H, 3.70; N,
10.29. Found: C, 52.96; H, 3.74; N, 10.49.
N- L2 - L2 rmethoxychenvl) ethvl < -N' - f2- f 4- (3chlor c she nvl/ Ithiazolvl. thiourea
A solution of 1-((2-(4-(330 chlorophenyl]thiazolyl)thiocarbamoyl] imidazole (0.92 g,
2.86 mmol) and 2-(3-methoxyphenyl)ethylamine (0.45 g, 2.86
AP/P/ 9 5 / 0 0 7 2 3 bad ORIGINAL
AP Ο Ο Ο 3 8 β
-235mmcl) in Ν, Ν-dimethylformamide (15 mL) was stirred at 90'C for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from EtOAc to provide 0.85 g (74%) of the titled product as a white solid:
mp 183-185'C;
C?. (K3r, cm'1)3172, 3024, 1569, 1515, 1466, 1319, 1287,
1260, 1220, 1067, 996, 775, 728, 604;
-H LXR (300 MHz, DMSO-dg) δ 11.66 (br s, IH), 9.20 (br s, IH), 7.81 (s, IH), 7.63 (m, 2H) , 7.35 (m, 2H), 7.16 (m,
IH), 6.73 im, 3H), 3.77 (m, 2H) , 3.64 (s, 3H), 2.86 (t, J=7 Hz, 2H);
MS (FD) m/e 403 (M+), 405 (M+2);
UV (EtOH) 280nm (£=23880), 202 nm (£=42912).
Anal. Calcd for C19H18N3OS2CI: C, 56.49; H, 4.49; N,
10.40. Found: C, 56.62; H, 4.50; N, 10.58.
Example 297
N-f2-(1-cvclohexenvl) ethvll -Ν' -(2-(4-(3chlorophenvl)11thiazolyl thiourea
A solution of 1-((2-(4-(3chlorophenyl]thiazolyl)thiocarbamoyl] imidazole (0.92 g,
2.86 mmol) and 2-(1-cyclohexenyl)ethylamine (0.37 g, 2.86 mmol) in N, N-dimethy lformamide (15 mL) was stirred at 90'C fcr 0.5 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The
p.'p/ 95 / 00723
AP Ο Ο Ο 3 8 8
-236crystallized from EtOAc to provide 0.7 g (65%) of the titled product as a white solid: mp 196-197‘C;
IP. (KBr, cm'1) 2939, 1557, 1514, 1469, 1287, 1202, 1062,
831, 784, 719, 661;
1H NMR (300 MHZ, DMSO-dg) 5 11.66 (br s, IH,, 9.17 (br s, IK), 7.85 (s, IH), 7.76 (m, IH,, 7.61 (s, IH), 7.37 (m,
2H), 5.41(br s, IH), 3.60 (m, 2H, , 2.20 (t, J=7 Hz, 2H) ,
1.87 (m, 4H), 1.46 (m, 4H);
MS (FD) m/e 377 (M+), 379 (M+2,;
UV (EtOH) 285nm (£=23385), 232 nm (£=18756), 202 nm (£=31779)
Anal. Calcd for C18H20N3S2CI: C, 57.20; H, 5.33; N, 11.12. Found: C, 57.04; H, 5.32; N, 11.09.
Example ,2g8
=.I.L2- [4-.1.2-nitrppher.vΠ thiazoIv 111hi0carbamovΠ imidazole
A solution of 1,11-thiocarbonyldiimidazole (0.41g, 2.3mmol) and 4-(3-nitrophenyl)-2-thiazoleamine (0.5g, 2.3 mmol) in acetonitrile (25 mL) was stirred at room temperature for 72 h and heated at 60‘C for 72 h. The resulting precipitate was collected by filtration to provide 0.51 g (68%) of the titled product:
MS (FAB) m/e 332 (M+H).
Anal. Calcd for C13H9N5O2S2: C, 47.12; H, 2.73; N, 21.13. Found: C, 47.35; H, 2.69; N, 21.03.
Csl
Γ**» c>
CD a, £
BAD ORIGINAL £
APO 0 0 3 8 8
-237Exarccle 299
N- (2-.(l-.cvclohexenvl' ethvll -N‘(2-f4- (3nitrsohenvllI1 thiazolyl thiourea
A solution of 1-((2-(4-(3nitrophenyl]thiazolyl)thiocarbamoyl] imidazole (0.5g, 1.5 mmol) and 2-(1-cyclohexenyl)ethylamine (0.19 g, 1.5 mmol! in Ν,Ν-dimethylformamide (15 mL) was stirred at 90'C for 0.75 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from EtOAc to provide 0.37 g (63%) of the titled product as a yellow solid:
mp 218-221’C;
IR (KBr, cm4) 3165, 3017, 2922, 1569, 1513, 1465, 1352, 1265, 1216, 1167, 1065, 877, 788, 713, 676;
:H NMR (300 MHz, DMSO-d6) δ 11.76 (s, 1H) , 8.85 (br s, 1H) ,
8.61 (s, 1H), 8.25 (d, J=8 Hz, 1H), 8.11 (d, J=8 Hz, 1H), 7.77 (s, 1H), 7.67 (m, 1H) , 5.42(br s, 1H) , 3.58 (m, 2H) ,
2.20 (t, J=7 Hz, 2H), 1.89 (m, 4H), 1.46 (m, 4H); MS (FD) m/e 388 (M*);
UV (EtOH) 286nm (£=22903), 265nm (£=23582), 237 nm (£=17806), 202 nm (£=24107)
Anal. Calcd for CISH20N4O2S2: C, 55.65; H, 5.19; N, 14.42. Found: C, 55.45; H, 5.14; N, 14.51.
Example 300
NuJ^n.^-TphlorpS-henvlIethvl] -Ν’ - (2- (4-cvano)thiazolvll
Lhigursa A solution of 1-((2-(4cyano]thiazolyl)thiocarbamoyl] imidazole (0.71 g, 3.0 mmol)
AP/P/ 9 5 / 0 0 7 2 3
BAD ORIGINAL Ά
AP 0 0 0 3 8 8
-238and 2-(4-chlcropher.yI' ethylamine (0.48 g, 3.0 mmol) in Λ’,Λ’dimethylformamide (20 mL) was stirred at 9CC for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from EtOAc to provide 0.4 g (41%) of the titled product as a tan solid:
mp 188-190’C;
IR (KBr, cm-1) 3396, 3110, 2226, 1586, 1518, 1490, 1353,
1248, 1087, 808, 766, 649, 517;
XK NMR (300 MHZ, DMSO-dg) δ 11.8 (s, lh’) , 8.43 (br s, IH) , 8.12 (s, IH), 7.33 (d, J= 8Hz, 2H) , 7.24 ;d, J= 8hz, 2H),
3.69 (m, 2H), 2.84 (t, J=7 Hz, 2H);
MS (FD) m/e 322 (M+);
UV (EtOH) 287nm (£=10775), 257 nm (£=17025), 206 nm (£=313 50) .
Example 301
Ν-.Γ2- (.4rmethixyphenyl.) ethvll -N' - (2 -f 4-cyanci thiazolyl] tfriwiea A solution of l-[(2-[4cyano]thiazolyl;thiocarbamoyl] imidazole (0.9 g, 3.8 mmol) and 2-(4-methoxyphenyl)ethylamine (0.59 g, 3.8 mmol) in N, X-dimethyIformamide (25 mL) was stirred at 90'C for 2 h. The reaction was coded to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from EtOAc to provide 0.66 g (55%) of the titled product as a yellow solid:
APZP/ 9 5 / 0 0 7 2 3 bad original £
AP 0 0 0 3 8 8
-239mp 185-190'C;
IP. (KBr, cm.-l) 3208, 3064, 2236, 1547, 1514, 1259, 1201, 1164, 1033, 886, 775, 748, 680;
:H NMR. (300 MHz, DMSO-dg) δ 11.8 (br s, IH) , 8.4 (br s, IH) , 8.1 (s, IH), 7.13 (d, J= 9Hz, 2H), 6.83 (d, J= 9Hz, 2H!, 3.68 (s, 3H), 3.64 (m, 2H), 2.77 (t, J=7 Hz, 2H> ;
MS (FD) m/e 318 (M+);
UV (EtOH) 2 = 4nm (£=12158), 258 nm (£=17248), 204 nm (£=30994) .
Example .3 ¢2
1-- 2-benzimldazolyl?thiocarbamoyl1 imidazole
A solution of 1,1'-thiocarbonyldiimidazole (8.9ig, 50 mmol) and 2-aminobenzimidazole (6.66g, 50 mmol) in acetonitrile (50 mL) was stirred at room temperature for 19 hours. The resulting precipitate was collected by filtration to provide 8.92 g (73%) of the titled product:
IR (KBr, cm1) 3058, 2621, 1623, 1580, 1509, 1469, 1445,
1355, 1290, 1252, 1212, 1153, 1099, 1081, 1048, 925, 898, 746, 659;
-H NMR (300 MHz, DMSO-dg) δ 13.24 (br s, 2H) , 8.52 (s, IH! ,
7.87 (s, IK', 7.57 (m, 2H), 7.33 (m, 2H), 6.96 (s, IH);
MS (FAB·) m/e 244 (M+1);
UV (EtOH) 35inm (£=18204), 283nm (£=13099), 227 nm (£=17339), 204 nm (£=31915) .
Example. 3Q3
Ν-Γ2- (2-chlorophenvl) .ethvl.] -N'_- (2-benzimidazolvl) thiourea
A solution of 1-((2benzimidazciyl)thiocarbamoyl]imidazole (1.22 g, 5.0 mmol) and 2-(2-chlorophenyl)ethylamine (0.81 g, 5.0 mmol) in N,NAP/P/ 9 5 / 0 0 7 2 3
BAD ORIGINAL fl
AP 0 0 0 3 8 8
-240dimethylformamide (20 mL) was stirred at 90'C for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from EtOAc to provide 0.67 g (40%) of the titled product as a white solid:
mp 166-169’C;
IR (K3r, cm'1) 3235, 1656, 1554, 1459, 1248, 1224, 1192,
7=4, 737, 629;
!h NMR (300 MHz, DMSO-dg) δ 11.95 (br s, IH) , 10.82 (br s,
IH! , 7.42 !m, 5H), 7.25 (ro, 2H), 7.12 (m, 2H), 3.83 (m,
2H), 3.05 (t, J=7 Hz, 2H);
MS (FD)'m/e 330 (M+);
UV (EtOH) 301nm (£=18044), 293 nm (£=18559), 266 nm (£=11113), 260nm (£=10441), 239 nm (£=8428), 206 nm (£=27 620).
Example 3.Q4
N.-.12-13-chlorophenyl) ethvl I-N'- (2-benzimidazolvl) thiourea
A solution of 1-((2benzimidazolyl) thiocarbamoyl]imidazole (1.22 g, 5.0 mmol) and 2-(3-chlorophenyl)ethylamine (0.79 g, 5.0 mmol) in N,Ndimethylformamide (20 mL) was stirred at 90*C for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from EtOAc to provide 0.24 g (14%) of the titled product as a white solid:
mp 171-177’C;
ΛΡ/Ρ/ 9 5 / 0 0 7 2 3
BAD ORIGINAL &
APO 0 0 3 8 8
-24 ΙΣΗ (KBr, cm’1) 3387, 1574, 1539, 1461, 1426, 1237, 1175, 734, 699, 477;
2H NMR (300 MHz, DMSO-dg) δ 11.18 (m, 2H) , 7.28 (m, 8H) , 7.06 (m, IH), 3.83 (m, 2H), 2.94 (t, J=7 Hz, 2H);
MS 'FD) m/e 330 (M+);
UV (EtOH) 293 nm (6=17219), 266 nm (6=9969), 26Cnm (6=9196), 240 nm (6=3196), 2C3 nm (ε=2“483).
Exazsle J.C.S
N-..'2- ^-ThlcrobherAd^thvI . -Ν' - ;2-benzimidazclvl) thiourea
A solution of 1-((2tenzimidazolyl)thiocarbamoyi]imidazole (1.22 g, 5.0 mmol) and 2-(4-chlorophenyl)ethylamine (0.79 g, 5.0 mmol) in N,xdimethylformamide (20 mL) was stirred at 90 °C for 2 h.
The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCI, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from EtCAc to provide 1.31 g (79%) of the titled product as a white solid:
mp 173-182'C;
IR (KSr, cm'1) 3168, 3031, 1668, 1562, 1494, 1470, 1327, 1221, 1174, 1090, 817, 777, 742, 657, 526, 457;
2H NMR (300 MHz, DMSO-dg) δ 12.18 (br s, IH), 10.36 (br s, IH), 7.52 (m, 2H), 7.22-7.38 (m, 7H), 3.76 (m, 2H), 2.89 (t, J=7 Hz, 2H);
MS (FD) m/e 330 (M+), 332 (M*2);
UV (EtOH) 3Clnm (6=21672), 293 nm (6=22296), 266 nm (6=13438), 26Cnm (6=12591), 206 nm (6=29310).
AP/P/ 9 5 / 0 0 7 2 3
BAD ORIGINAL
AP000388
-242Example 306
N-r2-(2-methoxyphenvl)ethvl)-Ν' -(2-benzimidazolyl) thiourea
A solution of 1-((2benzimidazolyl)thiocarbamoylJ imidazole (1.22 g, 5.0 mmol) and 2-(2-methoxyphenyl)ethylamine (0.82 g, 5.0 mmol) in ::. N-dimethylformamide (20 mL) was stirred at 90'C for 2 h.
The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer 10 was concentrated and the resultant solid was crystallized from EtOAc to provide 0.62 g (38%) of the titled product as a white solid:
m.p 176-184'C;
IR vK3r, cm1) 3035, 1644, 1539, 1495, 1463, 1331, 1246,
2203, 1025, 750, 454;
-H NMR (300 MHz, DMSC-c?6) 5 11.95 (br s, IH) , 10.32 (br s,
IH), 7.52 (m, 2H), 7.20 (m, 5H), 6.88 (m, 2H) , 3.75 (s, 3H)
3.70 (m, 2H), 2.88 (t, J=7 Hz, 2H);
MS (FD) m/e 326 (M+); 5«
UV (EtOH) 301nm (£=20950), 293 nm (£=21508), 265 nm CL (£=14212), 239 nm (£=9552), 204 nm (£=30277).
Example 3Q7
Ν-r 2 - (3 -methPXVPhenyl.) ethyllmN-'.- (.2-benz imidazoly1) thiourea 25 A solution of 1-((2benzimidazolyl)thiocarbamoyl]imidazole (1.22 g, 5.0 mmol) ar.d 2-(3-methoxyphenyl)ethylamine (0.78 g, 5.0 mmol) in N.N-dimethylformamide (20 mL) was stirred at 90*C for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer
BAD ORIGINAL
AP 0 0 0 3 8 β
-213was concentrated and the resultant solid was purified by chromatography on silica gel to provide 1.2 g (73%) cf the titled product as a white solid:
mp 161-167'C;
IR (KBr, cm’1) 2932, 1574, 1541, 1460, 1230, 1152, 1016, 737, 694, 577, 461;
NMR (300 MHz , DMSO-dg) δ 11.14 (br s, IH), 10.95 (br s,
IH), 7.30 im , 2h : , 7.16 (m, IH), 7.06(m. 2H), 6.87 (m, 2H)
6.75 (m, 2H) , 3.83 (m, 2H) 3.80 (s, 3H), 2.89 ' t, J = 7 Hz,
2H) ;
MS (FD) m/e 326 (K+);
UV (EtOH! 301nm (£=23757), 293 nm (£=24495), 265 nm (£=16068), 260 nm (£=14682), 239 nm (£=11477), 204 nm (£=36963) .
Exams i ¢...3 OS
N-(2-(4-methoxvchenvl)ethvll-N‘-(2-benzimidazolvl) thiourea
A solution of 1-((2benzimidazolyl)thiocarbamoyl]imidazole (1.22 g, 5.0 mmol) and 2-(4-methcxyphenyl)ethylamine (0.77 g, 5.0 mmol) in Ν,Ν-dimethylformamide (20 mL) was stirred at 90'C for 1 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was purified by chromatography on silica gel to provide l.lg (67%) of the titled product as a white solid:
mp 166-172’C;
IR (KBr, cm*1) 3416, 3195, 3065, 1575, 1543, 1511, 1464, 1243, 1176, 1037, 747, 442;
AP/P/ 9 5 / 0 0 7 2 3
BAD ORIGINAL ffl
AP Ο Ο Ο 3 8 8
-24410 :Η ΝΜΗ (300 MHz, DMSO-dg) δ 11.11 (br s, IH) , 10.95 (br s, IH), 7.36 (m, 2H), 7.20 id, J=8 Hz, 2H), 7.08(m, 3H), 6.82 id, J = 8 Hz, 2H) , 3.78 (m, 2H) 3.67 (s, 3H), 2.85 (t, J=7 Hz, 2H';
MS (FD) m/e 326 (M+);
UV (EtOH) 301nm (£=24618), 293 nm (£=25247), 265 nm (£=16716), 260 nm (£=15557), 203 nm (£=35060).
Example cvclohe?
~L·yΏ..£thy-l·)--R-, - (2-ber,zim.idazclvl) thiourea
A solution of 1-((2tenzimidazolyl)thiocarbamoyl]imidazole (1.22 g, 5.0 mmol) and 2-(1-cyclohexenyl)ethylamine (0.64 g, 5.0 mmol) in N,Ndimethylformamide (20 mL) was stirred at 90’C for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from EtOAc to provide 0.82 g (55%) of the titled product as yellow needles:
mp 178-180*0;
IR (KBr, cm1) 3182, 2922, 1576, 1540, 1421, 1271, 1232, 1033, 740, 450;
NMP. (300 MHz, DMSO-dg) δ 11.08 (br s, IH) , 11.07 (br s, IH), 11.02 'br s, IH), 7.36 (m, 2H) , 7.06(m, 2H), 5.51 (s, IH), 3.66 (m, 2H), 2.21 (t, J=7 Hz, 2H), 1.93 (m, 4H), 1.51 £ 2 L 0 0 / ς 6 /d/dV
AP Ο Ο Ο 3 8 6
-?45UV (EtOH) 301nm (ε=25279) , 292 nm (£=26214), 265 nm (£=15965), 259 nm (£=14734), 239 nm (£=11012), 206 nm (£=30 007) .
Anal. Calcd for Ci6H20N4S: C, 63.97; H, 6.71; N, 18.65.
Found: C, 64.25; H, 6.99; N, 18.63.
Example 310
1-1 (2-pyridYl)thiocarbamoyl! imidazole A solution of 1,1'-thiocarbonyldiimidazole (9.9 g, 50 mmol, and 2-aminopyridine (4.75 g, 50 mmol) in acetonitrile (50 mL) was stirred at room temperature for 72 h. The resulting solution was evaporated to a black oil and triturated with hexane. The remaining oily residue was placed under vacuum to provide 13.6 g of crude titled product as a black solid:
2H NMR (300 MHz, DMSO-dg) δ 8.89 (br s, IH) , 8.58 (m, IH) , 8.35 (m, IH), 7.80 (m, 2H), 7.40 (m, IH), 7.15 (m, IH),
6.95 (m, IH) ;
MS (FAB, m/e 204 (M+, weak)
Example 311
Ν-Γ2-(2-chlcrcphenvlJethvll-Ν'-(2-pyrldvl;thiourea
A solution of 1-[(2-pyridyl)thiocarbamoyl] imidazole (1.02 g, 5.0 mmol) and 2-(225 chlorophenyl)ethylamine (0.81 g, 5.0 mmol) in N,Ndimethylformamide (20 mL) was stirred at 90*C for 24 h.
The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant oil was purified by
AP/P! 9 5 / 0 0 7 2 3
BAD ORIGINAL fl
AP Ο Ο Ο 3 8 8
-:<ό· chromatography on silica gel to provide 0.21 g (14%) of the titled product as a yellow solid: mp 116 -12 2 ‘ C;
IR (KBr, cm-1) 3235, 1606, 1592, 1558, 1537, 1477, 1439,
1332, 1259, 1234, 1212, 1185, 1150, 1088, 1057, 861;
ςΗ NMR (300 MHz, DMSO-dg) δ 11.63 (m, IH), 10.53 (S, IH), 8.03 (m, IH) , 7.68 (m, IH), 7.41 (m, 2H), 7.30 (m, 2H),
7.07 (m, IH) , 6.96 (m, IH), 3.84 (m, 2H), 3.04 (t, J=7 Hz, 2H) ;
MS (FD) m/e 291 (M+) ;
UV (EtOH) 293 nm (£=14959), 266 nm (£=15723), 246nm (£=15174), 201 nm. (£=23 340).
Example 312
2-12^ GrDif.luorophenvl) ethylamine
2,6-Difluorophenylacetonitrile (15.8g, 100 mmol)was dissolved in tetrahydrofuran (75 mL) at room temperature. The solution was cooled in an ice bath and borane-THF complex (lOOmL, 100 mmol) was added dropwise over 15 minutes under nitrogen atmosphere. The ice bath was removed after borane addition was complete and the mixture was stirred at room temperature for 23 hours under nitrogen atmosphere. Saturated aqueous ammonium chloride solution (20 mL) was added dropwise with stirring over 30 minutes. The reaction mixture was filtered through diatomaceous earth, concentrated to an oil, redissolved in ethyl acetate/water, and adjusted to pH 1.0 with concentrated hydrochloric acid. The mixture was filtered through diatomaceous earch and the ethyl acetate layer extracted with IN hydrochloric acid (4 x 10 mL) . The combined acidic aqueous extracts were washed with ethyl
AP/P/ 9 5 / 0 0 7 2 3
AP υ Ο Ο 3 8 8
-247acetate (2 χ 50 rr.l) . Solid sodium chloride was added to the acidic aqueous extracts, adjusted to pH 9.0 with solid sodium bicarbonate ar.d 5N sodium hydroxide solution, and the mixture extracted with methylene chloride (7 x 50 mL).
The combined methylene chloride extracts were washed with brine solution, dried over anhydrous sodium, sulfate, filtered, and concentrated to yield 10.6g ί68%) of the titled product as a nearly colorless cil;
IR i'Ksr, cm-1) 2967, 2876, 1626, 1590, 1469, 1265, 1236,
1213, 1157, 1128, 1085, 1051, 1016, 956, 843 ;
1H NMR (300 KHz, CDCI3) δ 7.13 (m, IH) , 6.83 (m, 2H) , 2.89 (m, 2H), 2.80 (t, J=7 Hz, 2H) , 1.19 (s, 2H) ;
MS (FD) m/e 157 (M+, weak);
UV (EtCH) 265nm (£=650) , 2 60nm (£=674 ) , 204nm (£=7922 ) ;
TITRATION (66% DMF/H2O) pKa 9.06
Anal. Calcd for CgHgF2N: C, 61.14; H, 5.77; N, 8.91. Found: C, 60.88; H, 5.88; N, 8.63.
Example 313
N- F2-(2,6-difluorophenyl)ethvl)-Ν’ -f2-(4ethvl)thiazolvl)thiourea
A solution of 2-(2,6difluorophenyl)ethylamine(0.16 g, 1 mmol) and l-[(2-[4ethyl]thiazolyl) thiocarbamoyl] imidazole (0.24g, 1 mmol) in N,N-dimethylformamide (15 mL) was stirred at 90'C for 2
h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from EtOAc to provide 0.29 g (69%) of the titled product as a pale yellow solid:_
AP/P/ 95/00723
AP Ο Ο Ο 3 8 β
-248mp 157-158Ό;
IR (KBr, cm'1) 3178, 2972, 1584, 1502, 1469, 1340, 1351, 1293, 1267, 1212, 1075, 1014, 953, 787, 726, 6~2;
1Η NMR (300 MHz, DMSO-dg) δ 11.54 (br s, IH) , 9.75 (br s,
IH), 7.29 (m, IH), 7.01 (m, 2H), 6.5S is, IH), 3.77 (m,
2H1, 2.92 (t, J = 7 Hz, 2H), 2.45 (q, J=8 Hz, 2H), 1.05 (t,
J=9 Hz, 3H) ;
MS 'FD) m/e 327 (M4);
UV (EtOH) 292nm (£=18786) , 257nm (£=10105) , 202nm (£=19042) .0 Anal. Calcd for C14H25F2N3S2: C, 51.36; H, 4.62; N, 12.83. Found: C, 51.60; H, 4.78; N, 13.08.
Exapple 314
N-f2 - i2,.6-diflu.orophenvl)-e.Lhv.ll-N'- (2-ovridvl!thiourea
A solution of 2-(2,6-difluorophenyl)ethylamine (0.43 a, 2.7 mmol) and 1-[(2-pyridyl)thiocarbamoyl] imidazole (0.55 g, 2.7 mmol) in Ν,Ν-dimethylformamide (20 mL) was stirred at 90'C for 27 h. The reaction was coded to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant oil was purified by chromatography on silica gel to provide 0.08 g (10%) of the titled product as a pale yellow solid:
mp 157-160’C;
IR 'KBr, cm’1) 3226, 1605, 1539, 1466, 1332, 1260, 1236, 1138, 1100, 974, 899, 861, 774, 725, 635, 516;
:H NMR (300 MHz, DMSO-dg) δ 11.68 (br s, IH) , 10.53 (br s, IH), 7.99 (m, IH), 7.70 (m, IH), 7.28 (m, IH) , 7.04 (m,
4H), 3.82 (m, 2H), 2.97 (t, J=7 Hz, 2H) ;
AP/P/ 9 5 / 0 0 7 2 3
BAD ORIGINAL £
AP Ο Ο Ο 3 8 8
-249MS (FD) m/e 293 (Μ*);
UV(EtOH) 292rm (£=15506) , 266nm (£=16020) , 245ηη (£=14719)
1-f(2--2,6-31
Example 315 envl'ethvli thiocarbamoyl1 imida:
A solution of 1,1'-thiocarbonyldiimidazole :3.5 g, 48 mmol) and 2-(2,6-difluorophenyl)ethylamine (7.54 g, mmol) in acetonitrile (100 mL) was stirred at room temperature for 20 h. The solution was concentrated under reduced pressure and the resulting precipitate was collected by filtration and triturated with hexane to provide 16 g cf crude titled product as a brown solid:
IR !K3r, cm-1) 3129, 1565, 1468, 1355, 1259, 1203, 1120, 1065, 1031, 937, 930, 827, 787, 751, 664, 621, 499;
-H NMR (300 MHz, DMSO-dg) δ 10.50 (br s, IH), 8.29 (s, IH), 7.71 (s, IH), 7.35 ,’m, IH), 7.04 (m, 3H), 3.85 (m, 2H) , 3.0 :m, 2H!;
MS (FAB) m/e 268 ·Μ=Η);
uV(EtOH) 280nm (£=4068) , 250nm (£=4341) , 201nm (£=15062) /p/ 95/00723 a,
Example 31$
N-f 2- :1-cyclohexenyl)ethvll -N’-f2-(6chloro?pyrazinyl?thiourea A solution of 2-amino-6-chloropyrazine (2.59 g, mmcl! and 2-(1-cyolohexenyl)ethylisothiocyanate (3.34 g, 20 mmol) in N, N-dimethylformamide (25 mL) was stirred at 95 °C for 27 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was
BAD ORIGINAL
AP Ο Ο Ο 3 8 8
-25Cpurified by chromatography cn silica gel and crystallized from EtOAc tc provide 0.44 g (7%) of the titled product as white needles:
mp 170-17l'C;
IR (K3r, cm--) 3207, 2926, I5S4, 1514, 1414, 1295, 1161,
1005, 866, 714, 459 ;
ΣΗ NMR (300 MHz, DMSO-dg) δ 11.08 (br s, IH) , 10.02 (br s, IH), 8.49 (s, IH), 8.29 (s, IH), 5.48 'br s, IH), 3.64 (m, 2H), 2.21 (t, J = 7 Hz, 2K), 1.90 (rc, 4H) , 1.49 (m, 4H);
MS (FD) m/e 296 (M*), 298 (M*2);
UV (EtOH) 327nm (£=12429), 266 nm (£=17577)
Anal. Calcd for C13H17N4SCI: C, 52.60; H, 5.77; N, 18.87. Found: C, 52.89; H, 5.89; N, 19.11.
Example 317
N-I2- (2, 5-difluoropher.vi: ethvl] -N‘-f2-(6me/thyl)pyridvll thiourea A solution of 1-((2-(2,6difluorophenyl) ethyl) thiocarbamoyl] imidazole (0.53 g, 2 mmol) and 2-amino-6-methylpyridine (0.22g, 2 mmol) in N,Ndimethylformamide (20 mL! was stirred at 90 *C for 3 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCi, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from EtOAc to provide 0.14 g (23%) of the titled product as nearly colorless prisms:
mp 187-189'C;
IR (KSr, cm’1) 3195, 1612, 1544, 1468, 1451, 1380, 1293,
1269, 1230, 1192, 1160, 1072, 950, 788, 722, 635, 501;
AP/P/ 95/00723
AP 0 0 0 3 8 8
-251 -
iH NMR .(3 00 MHz, DMSO -dg) 6 11.83 (br s, IH), 10.44 (br s,
IH), 7.56 (t, J= 8 Hz, IH) , 7.26 (m, IH), 6.98 (m, 2H ) ,
6.87 (d, J = 8 Hz, IH) , 6.79 (d, J=8 Hz, IH), 3 .87 (m. 2H),
2.94 (t, J=7 Hz, 2H, , 2.11 (s, 3H);
MS (FD) m/e 307 (M*) ;
UV(EtOH) 296nm (£=12052) , 265nm (£=10578 ) , 246nm (£=10257, Anal. Calcd for C15K15F2N3S: C, 58.62; H, 4.92; N, 13.67. Found: C, 58.35; H, 4.98; N, 13.39.
Example 318
N- f 2- f 1 -cyclchexenyl-? .ethvl ]-N'-f2-(3,5dlmethvl/pyrazinvlI thiourea A solution of 2-amino-3,5-dimethylpyrazine (0.62 g, 5 mmol) and 2-(1-cyclchexenyl)ethylisothiocyanate (0.84 g, 5 mmol) in N, Λ’-dimethylformamide (20 mL) was stirred at 90’C for 24 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant oil was purified by chromatography on silica gel to provide 0.27 g (19%) of the titled product as an off-white solid: mp 100-103'C;
IR (KBr, cm-1) 3387, 2929, 1515, 1329, 1214, 1164, 1014, 966, 907;
!h NMR (300 MHz, DMSC-dg) δ 10.57 (br s, IH), 9.12 (br s,
1Η), 7.91 (s, IH), 5.44 (br s, IH), 3.61 (m, 2H), 2.47 (s, 3H), 2.35 (s, 3H), 2.18 (t, J=7 Hz, 2H), 1.90 (m, 4H) , 1.4S (m, 4H);
MS (FD) m/e 290 (M+);
frplPl 90/007 2 3 bad original $
APO 0 0 3 8 8
-252UV (EtOH) 320nm (£=11659), 265 nm (£=16153), 2C1 nm (£=11795)
Anal. Calcd for C15H22MS: C, 62.03 ; H, 7.63; N, 18.29. Found: C, 62.06; H, 7.65; N, 18.58.
Sxaagle.. 315,
N-12 - (2,6-difluoropheny1 ' ethvl' -N*-F2-(5tri fluorcmeThvll pyridvl thiourea
A solution of 1-((2-(2,β10 difluorophenyl'ethyl)thiocarbamoyljimidazole (1.07 g, 4 mmol) and 2-aminc-5-trifiuoromethylpyridine (0.65 g, 4 mmol) in N, N-dimethylformamide f20 mL) was stirred at 95’C for 25 h. The reaction was coded tc room temperature, poured into ethyl acetate, washed with water, IN aqueous
HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was purified by chromatography on silica gel to provide 0.26 g (18%) of the titled product as a white solid:
mp 148-152‘C;
20 IR (KBr, cm’1) 3165, 3033, 1619, 1600, 1543, 1470, 1332,
1248, 1189, 1160, 1138, 1106, 1079, 964, 886, 776, 669,
603, 435; ^H NMR (300 MHz, DMSO-dg) δ 11.42 'br s, IH) , 10.94 (br s,
IH) , 8.36 (s, IH) , 8.03 (m, IH) , 7.23 (m, 2H> , 7.02 (m,
25 2H), 3.82 (m, 2H), 2.98 (t, J=7 Hz, 2H);
MS (FD) m/e 361 (M+);
UV(EtOH) 297nm (£=18455), 253nm (ε=14“£2), 20inm (£=15765) Anal. Calcd for Cidd^Sd5 '· C, 49.86; H, 3.35; N, 11.63. Found: C, 49.59; H, 3.28; N, 11.35
BAD ORIGINAL
AP Ο Ο Ο 3 8 8
-253Examcle 320 lL-72-L2^ 6-difluorcphenvl)ethvll -Ν' - '2- '5chloro)pvridvl!thiourea A solution of 1-((2-(2,6difluorophenyl) ethyl) thiocarbamoyl] imidazole (1.07 g, 4 mmol) and 2-amino-5-chloropyridine (0.53 g, 4 mmcl) ir. ::,::dimethylformamide (20 mL) was stirred at 90‘C for 22 h.
The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was cry-stallized from EtCAc to provide 0.65 g t52%) cf the titled product as a tan solid:
mp 172-175’C;
IR (K3r, cm’1) 3233, 1597, 1557, 1529, 1468, 1340, 1308, 1265, 1231, 1190, 1112, 1072, 950, 857, 834;
^H NMR '300MHz, DMSC-dg) δ 11.19 (m, IH), 10.67 (s, IH), 8.03 (s, IH) , 7.82 (m, IH), 7.30 (m, IH) , 7.13 (m, IH),
7.03 im, 2H) , 3.79 (m, 2H) , 2.96 (t, J = 7 Hz, 2.H) ;
MS (FD) rn./e 327 (M+), 329 (M+2);
UV (EtOH) 324nm (£=13180) , 274nm (£=23154) , 253 nm (£=15998), 201 nm (£=19019)
Example 321
N- f2 - (2,6-difluorophenyl)ethvll-N1-f2-'5methvl) pyridylithiourea A solution of 1-((2-(2,6difluorophenyl) ethyl) thiocarbamoyl]imidazole (1.33 g, 5 mmol) and 2-amino-5-methylpyridine (0.54 g, 5 mmcl) in ::,::dimethylfcrmamide (20 mL) was stirred at 90'C for 7 h. The reaction was cooled to room temperature, poured into ethyl £2/00/96 /d/dV
BAD ORIGINAL
AP 0 0 0 3 8 8
-254acetate, washed with water, IN aqueous KC1, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from EtOAc to provide 0.63 g (86%) of the titled product as yellow crystals':
mp 195-196’C;
IP. (KBr, cm'1) 3230, 1611, 1535, 1492, 1468, 1334, 1274, 1236, 1190, 1111, 1065, 957, 821, 777, 716, 657, 608, 513; 1H NMR (300 MHZ, DMSO-dg) 6 11.59 (br s, IH) , 10.44 (br S, IH'· , 7.83 (br s, IH) , 7.53 id, J = 8 Hz, IH) , 7.30 (m, IH) , 7.02 (m, 3H), 3.80 (m, 2H5, 2.96 (t, J=7 Hz, 2K), 2.16 is, 3H) ;
MS (FD) m/e 307 (M+);
UV(EtCH) 297nm (£=5129) , 263nm (£=7508 ) , 247nm (£=53 83)
Anal. Calcd for C15H15F2N3S: C, 58.62; H, 4.92; N, 13.67. Found: C, 58.36; H, 4.98; N, 13.73.
Exarcle 3,22
N-i2-i2,6--difluQrophenyl)e.thyl]-N,-f2-(5bromo)ovrazinvl1 thiourea A solution of 1-((2-(2,6difluorophenyl) ethyl)thiocarbamoyl] imidazole (1.33 g, 5 mmol) and 2-amino-5-bromcpyrazine (0.87 g, 5 mmol) in Ν,Νdimethylformamide (20 mL) was stirred at 95C for 26 h.
The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was purified by chromatography on silica gel to provide 0.31 g (17%) of the titled product as a white solid:
mp 175-178 C;
AP/P/ 9 5 / 0 0 7 2 3
BAD ORIGINAL ffl
AP Ο Ο Ο 3 8 8
-255IR (KBr, cm'1) 3200, 1596, 1560, 1526, 1469, 1441, 1324, 1259, 1179, 1161, 1114, 1012, 962, 899, 874, 788, 30, 66, 601;
1H NMR '300 MHz, DMSO-dg) δ 10.98 (br s, IH), 10.51 (br s,
IH! , 8.33 (s, IH), 8.24 ( s, 1H(, 7.31 (m, IH), 7.04 (m,
2H), 3.81 (m, 2H), 2.97 MS (FD) m/e 372 (M+), 374 UV ’EtOH) 333m (£=10125 ) , it, C=7 Hz, 2H'; (M+2 ); 275r.m (£=22 57 0) , 201 nm (£=163 01
Anal. Calcd for CijHuBrF 2N'S: C, 41.84; H, 2.97; N,
15.01. Found: C, 42.10; H, 3.12; N, 14.7 ’3 .
Example. 122
Ν- (2- 2, 6-difluoroohenvl( ethvl i-N-r2-'6ethvl)pvridvl1 thiourea A solution of 1-((2-(2,6difluorophenyl) ethyl) thiocarbamoyljimidazole (1.33 g, 5 mmcl) and 2-amino-6-ethylpyridine (0.61 g, 5 mmol) in Ν,Νdimethylformamide (20 mL) was stirred at 95'C for 21 h.
The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from EtOAc tc provide 0.63 g (39%) of the titled product as dense yellow crystals:
mp 147-148'C;
IR (KSr, cm’1) 2972, 1609, 1541, 1468, 1344, 1292, 1265, 1225, 1155, 1073, 951, 804, 786, 727, 692, 635, 501;
*.H .NMR (300 MHz, DMSO-dg) 5 11.97 (m, IH), 10.48 (br s, IH), 7.59 (t, J = 8 Hz, IH) , 7.27 (m, IH) , 6.98 (m, 2H) , 6.89 id.
£ Z Z. 0 0 / ς θ /d/dV bad original ,ΑΡ,Ο 0 0 3 8 8
-256J=8 Hz, IH), 6.80 (d, J=8 Hz, IH), 3.87 (m, 2H), 2.95 it, J=7 Hz, 2H), 2.44 (q, J=8 Hz, 2H), 0.93 (t, J= 8 Hz, 3HI; MS (FD) m/e 321 <M+);
UV(EtOH) 296nm (€=17512) , 266nm (¢=15047 ) , 246nm (€=14627 ) ,
201nm (€=16211)
Anal. Calcd for C16H17F2N3S: C, 59.80,- H, 5.33; N, 13.07. Found: C, 60.04; H, 5.3S; N, 13.22.
Example 324
N-f 2 - (2,6-dif luorophenvl,' ethvll-N‘ -(2-(6chloro'cvrazinvlthiourea
A solution of 1-((2-(2,6difluorophenyl) ethyl)thiocarbamoyl] imidazole (4.0 g, 15 mmol) and 2-amino-6-chloropyrazine (1.96 g, 15 mmol) in
N,N-dimethylformamide (25 mL) was stirred at 95*C for 18 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was purified by chromatography on silica gel to provide 0.7 g (14%) of the titled product as a light yellow solid: mp 175-180’C;
IR (KBr, cm*1) 3232, 1588, 1512, 1468, 1414, 1296, 1240, 1163, 1097, 1004, 981, 869, 777, 714, 659, 459;
*H NMR (300 KHz, DMSO-dg) δ 11.07 (br s, IH), 10.07 (far s,
IH), 8.50 (s, IK), 8.28 (s, IH), 7.28 (m, IH), 7.00 (m,
2H), 3.85 (m, 2H), 2.95 (t, J=7 Hz, 2H) ;
MS (FD) m/e 328 (M+), 330 (M+2);
UV (EtOH) 327nm (€=10851), 265nm (€=14817), 201 nm (€=16442)
AP/P/ 9 5 / 0 0 7 2 3
BAD ORIGINAL
J
AP Ο Ο Ο 3 8 8
-257EXar.pls 2 25
Σίτ12- 12..-pyridyl) ethvl! -Ν' - Γ2- )4-cr/ano' thlazclvl1 thl:
A solution of 1-((2-(4cyano]thiazolyl)thiocarbamoyl] imidazole (2.35 g, 11 m. and 2-(2-pyridyl;ethylamine il .29 g, 10 mmol) in N,;.*dimethyIformamide (25 mL) was stirred at 95'C for 2 h.
reaction was cooled to room temperature, poured into ethyl acetate, washed with water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue purified by chromatography on silica gel to provide 0.4 g /14%) of the titled product as a yellow solid: mp 16 0 ' C;
1?. (E3r, cm-1) 3165, 3100, 2996, 2234, 1540, 1489, 1432, 1305, 1266, 1219, 1159, 1132, 999, 904, 817, 758, 574, 425; -H NMR (300 MHz, DMSO-dg) 5 11.88 (br s, IH), 8.67 (br s, IK), 8.49 (d, J=4 Hz, IH), 8.11 (s, IH), 7.69 im, IK), .23 (m, 2H), 3.87 (m, 2H), 3.01 (t, J=7 Hz, 2H) ;
MS (FD) m/e 289 <M+);
UV (EtOH) 288nm (£=10826), 257 nm (£=19925), 205 nm (£=28658) .
AP/P/ 9 5 / 0 0 7 2 3
Example 326
N- .(2..-'2, 6-dif luorophenyl) ethvl) -Ν' -(2-(4methvllpvridvl)thiourea A solution of 1-((2-(2,6difluorophenyl)ethyl)thiocarbamoyl]imidazole (1.33 g, 5 mmol) and 2-amino-4-methyIpyridine (0.54 g, 5 mmol) in .V, dimethylformamide '20 mL) was stirred at 90’C for 3 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer
BAD ORIGINAL £
APO 0 0 3 8 8
-258was concentrated and the resultant solid was crystallized from EtOAc to provide C.49g -,32%) of the titled product as yellow needles:
mp 168-170'C;
IF. (KBr, cm1) 3233, 1616, 1536, 1465, 1335, 1262, 1191,
1104, 959, 815, 783, 719, 653, 442;
NMR (300 MHz, DMSO-dg) 8 11.74 (br S, 1H), 10.44 (br s, 1H), 7.85 (d, J=5 Hz, 1H), 7.27 (m, 1H), 7.02 (m, 2H), 6.88 (s, 1H), 6.80 (d, J=5 Hz, 1H) , 3.80 (m, 2H), 2.96 (t, J=7
Hz, 2H!, 2.20 (s, 3H';
MS (FD) rn/e 307 (M+i ;
UViEtCHJ 290nm (£=16210 ; , 266nm (£=15920) , 24Snm (£=13211) , 2C2nm (£=13211) '-5 Sxapcle. 221 ί luorogher.YlJ g tM. lciL'-r L2-Liz pyridyl1 thiourea
A solution of 1-((2-(2,6difluorophenyl)ethvl)thiocarbamoyl]imidazole (1.33 g, 5 20 mmol) and 2-amino-4-ethylpyridine (0.61 g, 5 mmol) in Ν,Νdimethyl f ormamide (20 mL) was stirred at 95'C for 3 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from EtOAc to provide 0.32 g (20%) of the titled product as a light brown solid:
mp 140-142'C;
IR (KBr, cm’1) 2939, 1615, 1590, 1536, 1469, 1341, 1267,
1189, 1104, 1064, 960, 868. 826, 781, 759, 721, 668, 652;
AP/P/ 9 5 / 0 0 7 2 3 bad original £
AP Ο Ο Ο 3 8 8
-259-
1= ;;vr <300 MHz, DMSO-dg) δ 11.7 4 'br S, IK', 10.42 «'br s
IK) • , 7 . 87 id, J=5 Hz, IH! , 7.29 hm, IH) , 6.99 (m, 2H! , 6.
(s, IH) , 6.84 (d, 0 = 5 Hz, IH), 3.81 im, 2H), 2.95 it, O=~
U-7 * · t 2H) , 2.49 (q, O=S Hz, 2H), 1.09 it, 0=8 Hz, 3H);
5 MS FD) m/e 321 (M+);
U V · EtOH ) 2 90nm (£=1 3247 ) , 266nm (£=18045) , 2 4 6.0m (£=15212),
2C2nm (£=27 517)
Anal. Calcd for C10K17F2N3S: C, 59.79; H, 5.33; N, 13. C~. Found: C, 59.50; H, 5.31; N, 12.87.
P y A ’r 1 β Ο Ο l-ί(2-i2-ovridyl’ethvl)thiocarbamoyl] Imidazole
A solution cf 1,1 ’-thiocarbonyldiimidazole ‘9.9 g, 50 mmol) and 2 - (2-pyridyl) ethylamine «6.43 g, SOmmcl; ir. acetonitrile (120 mL) was stirred at room temperature fcr 24 h. The solution was concentrated under reduced pressure and the resulting brown oil was triturated with ethyl ether. The remaining oil was placed under vacuum to provide 10.7 g of crude titled product as a black solid:
IR KBr, cm-1) 3125, 2930, 2098, 1548, 1477, 1437, 1363, 1329, 1234, 1221, 1098, 1063, 1030, 925, 828, 750, 661,
620;
-H NMR (300 MHz, DMSO-dg) δ 10.35 (br s, IH) , 8.48 tin, IH. , 8.33 (s, IH), 7.76 (s, IH), 7.72 (m, 2H), 7.25 (m, 2H),
3.95 (m, 2H) , 3.1 (m, 2.H) ;
MS FA3! m/e 233 (M+H);
UV(EtCH) 267nm (£=5516) , 261nm (£=6306 ) , 256nm (£=6220) ,
203nm (£=14929)
AP/P/ 9 3/ 0 0 7 2 3
AP Ο Ο Ο 3 8 8
-26010
Ν- ί 2 - (Zrpyridyll ethvl 1 -Ν-12- i S.-bromo) pyrazinyl 1 thiourea
A solution of 1-((2-(2pyridyl!ethylithiocarbamovl] imidazole (1.16 g, 5 mmol) and
2-aminc-5-bromopyrazine (0.87 g, 5 mmcl) in N,Ndimethylfcrmamide '20 mL? was stirred at 95’C for 27 h.
The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue purified by chromatography on silica gel and crystallized from EtOAc to provide 0.13 g (7%) of the titled product as a tar. solid:
IR (K5r, cm-1) 3186, 1588, 1558, 1517, 1479, 1439, 1356, 1325, 1283, 1268, 1220, 1185, 1156, 1100, 1083, 1013, 996, 900, 86, 800, 760, 716, 569, 511, 431;
!h NME (300 MHz, DMSO-dg) δ 10.93 (br s, IH) , 10.74 (br s, IH!, 8.54 (d, J=5 Hz, IH), 8.31 (s, IH), 8.28 (s, IH), 7.69 (m, IH), 7.28 (m, IH) ,. 7.21 (m, IH) , 3.96 (m, 2H) , 3.05 (t, J=7 Hz, 2H);
MS (FD) m/e 337 <(M+), 339 (M+2);
UV (EtOH! 333nm (£=10984), 270 nm (£=25064).
Anal. Calcd fcr Ci2Hl2BrNsS: C, 42.61; H, 3.58; N, 20.71. Found: C, 42.41; H, 3.83; N, 20.54 .
Example.J3Q
N-r2-(2.6-difluorophenyl)ethyl]-Ν' -Γ2-(5ohl-crgj pyrazinyl 1 thiourea A solution of 1-((2-(2,6difluorophenyl)ethyl)thiccarbamoyl] imidazole (1.33 g, 5 mmol) and 2-amino-5-chloropyrazine (0.65 g, 5 mmol) in N,NAP/P/ 9 5 / 0 0 7 2 3
BAD ORIGINAL
AP Ο Ο Ο 3 8 8
-261dimethylformamide ι20 mL) was stirred at 95’C fcr 24 h.
The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was purified by chromatography on silica gel and crystallized from EtOAc to provide 0.1 g (6%) of the titled product as a white solid: mp 170-171’C;
IR (K5r, cm'1) 3199, 3070, 1593, 1563, 1529, 1463, 1443,
1418, 1327, 1263, 1134, 1166, 1123, 1016, 779;
:H NMR (300 MHz, DMSO-dg) 5 11.00 (br s, IH), 10.53 (br s, IH), 8.33 (s, IH), 8.19 (s, IH), 7.30 (m, IH) , 7.04 (m,
2H), 3.81 (m, 2H) , 2.96 (t, J=7 Hz, 2H);
MS (FD) m/e 328 (M+), 330 (M+2);
UV (EtOH) 332nm (£=10097, , 274nm (£=22879,
Anal. Calcd for C13H11CIF2N4S: C, 47.49; H, 3.37; N,
17.04. Found: C, 47.54; H, 3.45; N, 17.19.
Example 331
1-f (2-(5-ethcxv carbonvl) thiazolyl) thiocarbamoyl 1 Imidazole
A solution of 1,1'-thiocarbonyldiimidazole (8.9 g, 50 mmol) and 2-amino (5-ethoxy carbonyl) thiazole (8.9 g, mmcl) in acetonitrile (600 mL) was stirred at 50’C for 20 h. The resulting precipitate was collected by filtration to provide 6.5 g (40%) of the titled product, mp 208-210'C (d).
IR (KEr, cm1) 3205, 3176, 3146, 3115, 1708, 1557, 1470, 1352, 1298, 1244, 1225;
-H NMR (300 MHz, DMSO-dg) δ 13.2 (br s, IH), 8.1 (s, IH) ,
7.9 (s, IH), 7.6 (s, IH), 7.1 (s, IH), 4.2 (q, 2H), 1.3 (t,
AP/P/ 95/0 0723
AP Ο Ο Ο 3 8 8
-262MS (FD) m/e (no correct pk) (M*);
UV (EtOH) 349 nm (£=4746), 269 nm (£=8713), 209 nm. (£=21033). Anal. Calcd for C10H1CN4O2S2: C, 42.54 H, 3.57; N, 19.84. Found: C, 42.37; H, 3.55; N, 19.59.
Example 332
M-j2-..(locvc.lDhex£Dy-l)ethyl) -N’-i2 - (5-ethoxy carbonvll-Lhiazolvl 1 thiourea A solution of 1-[(2-[5-ethoxy carbonylthiazolyl)thiocarbamoyl] imidazole :1.12 g, 4.0 mmol) and 2-(1-cyclohexenyl!ethylamine (0.5 g, 4.0 mmol) in ::, /.’-dimethylformamide (40 mL) was stirred at 90 °C for 1 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acetate to provide 0.790 g (56%) of the titled product: mp. 197-193‘C;
IR (KBr, cm1) 3243, 3121, 3044, 2991, 2925, 1707, 1582,
1543, 1453, 1190;
1H NMR (300 MHz, DMSO-cfg) δ 12.0 (br S, IH), 8.5 (br s, IH) ,
7.9 is, IH), 5.5 (s, IH), 4.3 (q, 2H), 3.6 (m. 2H), 2.2 (t, J=7 Hz, 2H), 1.9 (m, 4H), 1.5 (m, 4H), 1.3 (t, J=7 Hz, 3H); MS (FD) m/e 339 (M+);
UV (EtCH) 262nm (£=17510), 205 nm (£=19237).
.Anal. Calcd for C15H21N3O2S2: C, 53.07; H, 6.23; N, 12.38. Found: C, 53.31; H, 6.44; N, 12.42.
AP/P/ 9 5 / 0 0 7 2 3
BAD ORIGINAL
AP Ο Ο Ο 3 8 8
-263Example 333
Ν-i2-shenethvl? -Ν' - '2m._.( 5-ethoxy carbonyl' thiazolyl ( thiourea
A solution of 1 - [ !2-[5-ethoxy carbonyl]thiazolyl)thiocarbamoyl] imidazole (1.1 g, 4.0 mmol) and 2-(1-phenyl)ethylamine (0.6 g, 4.0 mmol) dimethylformamide (40 mi) was stirred at 90’C for 1 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, IN aqueous HCI, water, saturated sodium bicarbonate, and trine. The organic layer was concentrated and the residue crystallized from; ethyl acetate to provide 1.C7 g (80%) of the titled product: mp. 174-175‘C;
IP. (KBr, cm’1) 3340, 3253, 3124, 3C56,
1537, 1454, 1252, 1222;
1H NMR (300 MHz, DMSO-dg) δ 12.0 (br S
7.9 (s, IH), 7.3 (m, 5H), 4.3 (q, 2H) , 3.8 (m, 2H), 2.9 ,t C=7 Hz, 2H), 1.3 (t, J=7 Hz, 3H);
MS (FD) m/e 335 (M+);
W (EtCK) 262nm (€=19184), 206 nm (£=26117).
Anal. Calcd for C15H17N3C2S2: C, 53.71; K, 5.11; N, 12.53 Found: C, 53.48; H, 5.10; N, 12.68.
17C7, 1652, 1579,
IH), 8.7 (br s, IH) ,
AP/P/ 9 5 / 0 0 7 2 3
Example 334
N- r2- (l-cvclohexenvl?ethvll-Ν' -(2-(5-chlorc( pvridvl1 thiourea
A solution of 2-aminc-5-chlcropyridine (1.28 g, 10.C mmol) and 2-(1-cyclchexenyi?ethylisothiocyanate (1.67 g, 10.0 mmol) in Ν,Ν-dimethyiformamide (30 mi! was stirred at 90’C for 1 h. The reaction was cooled to room
AP Ο Ο Ο 3 8 β
-264The residue was purified by HPLC to provide 0.560 g (19%) of the titled product: mp. 166-167'C;
IR (KBr, cm’1) 3455, 3159,1599, 1555, 1534, 1476;
1H NMR (300 MHz, DMSO-dg) δ 11.1 (br S, IH) , 10.7 (s, IH) ,
6.2 (d, IH), 7.9 (m, IH), 7.2 (d, IH), 5.5 (s, IH), 3.6 (m, 2H), 2.2 (t, J=7 Hz, 2H), 1.9 (m, 4H), 1.5 (m, 4H);
MS (FD) m/e 295 (M+);
UV (EtOH) 3C5nm (£=12139), 273nm (£=15905) , 244 nm (£=25052).
Anal. Calcd for C14H18N3SCI C, 56.84; H, 6.13; N, 14.20. Found: C, 56.59; H, 6.00; N, 14.09.
Example .335
Ntf-2.r L2-chiorophenyl) ethvl) -N* - f 2- (5-chloro)pvridvl) thiourea
A solution of N-[2-(2-chlorophenyl)ethyl]-Ν'thiocarbamoyl imidazole (1.3 g, 5.0 mmol) and 2-amino-5chloro pyridine (0.65 g, 5.0 mmol) in X, AT-dimethylformamide (25 mL) was stirred at 100'C for 1 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water and brine. The organic layer was concentrated and the residue triturated with hexane to provide 0.83 g (55%) of the titled product: mp 178-179’C;
2Η NMR (300 MHz, DMSO-dg) δ 11.2 (m, IH) , 10.7 (s, IH), 8.1 (m, IH), 7.5 (m, IH), 7.4 (m, 2H), 7.2 (m, 2H), 7.1 (d,
IH), 3.8 (m, 2H), 3.1 (t, J=7 Hz, 2H);
MS (FD) m/e 325 (M+);
IT/ (EtOH) 305nm (£=12931), 273 nm (£=22583), 253 nm (£=16558)
201 nm (£=25277) .
AP/P/ 9 5 / 0 0 7 2 3
BAD ORIGINAL
AP Ο Ο Ο 3 θ 8
-265Anal. Calcd for C14H13N3SCI: C, 51.54; Η, 4.02; Ν, 12.88. Found: C, 51.26; Η, 3.99; Ν, 12.79.
Example 336
H-CYClPhexegyD-gLhvll-Ν'-ί3-iS-chloro’cvridazinyll thiourea
A solution of 3-amino-6-chloropyridazine (1.3 g, 10.0 mmol) and 2- (1-cyclohexenyl)ethylisothiocyanate (ll67 g, 10.0 mmol) in N,N-dimethylformamide <20 mL) was stirred at 90 °C for 1.5 h. The reaction was ccoied to room temperature and concentrated under vacuum to remove solvent. The residue was purified by HPLC to provide 0.220 g (7.5%) of the titled product:
mp. 149-153’C;
pKa in (66% DMF) 12.8;
IR (KBr, cm1) 3203, 3072, 2935, 1599, 1565, 1520, 1424, 1351, 1308, 1280, 1184, 1147, 1073;
!h NMR (300 MHz, DMSO-dg) 8 11.1 (m, IH) , 10.9 (s, IH), 7.8 (d, IH), 7.6 (d, IH), 5.5 (S, IH), 3.7 (m, 2H), 2.2 (t, J=7 Hz, 2H), 1.9 (m, 4H), 1.5 (m, 4H);
MS (FD) m/e 296 (M+);
UV (EtOH) 275nm (£=23066) .
Anal. Calcd for C13H17N4SCI C, 52.60; H, 5.77; N, 18.87. Found: C, 52.85; H, 5.84; N, 19.15.
AP/P/ 9 5 / 0 0 7 2 3
Example 337
N-6-difluorophenyl) ethvl) -Ν' - Γ3-(6chloro)pyridazinyl) thiourea A solution of N-[2-(2, 6-difluorophenyl)ethyl]N'-thiocarbamoyl imidazole (1.33 g, 5.0 mmol) and 3-amino30
APO00388
-266dimethylformamide (20 mL) was stirred at 80*C for 19 h.
The reaction was cooled to room temperature, poured into ethyl acetate, washed with water and brine. The organic layer was concentrated and the residue was purified by HPLC to provide 0.12 g (7.5%) of the titled product: mp 187-189‘C;
IR (KBr, cm'1) 3199, 3055, 1626, 1593, 1555, 1522, 1469,
1425, 1348,1313, 1263;
NMR (300 MHz, DMSO-dg) δ 11.2 (m, IH) , 10.9 (S, IH) , 7.9 id, IH), 7.6 <d, IH), 7.3 (m, IH!, 7.1 (m, 2H), 3.9 (m,
2H) , 3.0 (t, 0 = 7 Hz, 2H) ;
MS (FD! m/e 328 (K+); pKa in (66% DMF) 12.73;
UV (EtOH) 277nm (€=20141), 252 nm (€=12935), 201 nm (€=17891).
Example 338
N-(2-.(2, g-difluorophenynethvlI-N'-n-femethoxy)pyridazinyl1 thiourea
A solution of N-[2-(2, 6-difluorophenyl) ethyl]N’-thiocarbamoyi imidazole (0.8 g, 3.0 mmol) and 3-amino-6methoxy pyridazine (0.4 g, 3.0 mmol) in Ν,Νdimethylformamide (20 mL) was stirred at 70‘C for 19 h.
The reaction was cooled to room temperature, poured into ethyl acetate, washed with water and brine. The organic layer was concentrated and the residue was precipitated with diethyl ether to provide 0.235 g (24%) of the titled product:
mp 193-196*0;
IR (KBr, cm'1) 3222, 3084, 1628, 1586, 1560, 1531, 1468,
1423, 1356, 1310, 1266;
AP/P/ 9 5 / 0 0 7 2 3
BAD ORIGINAL Λ
APO Ο Ο 3 8 8
-267-Η iiMR (300 MHz, DMSO-dg) δ 11.45 (m, IH) , 10.7 (s, IH! , 7.42 (d, J = 10 Hz, IH), 7.28 (m, IH) , 7.21 (d, J=10 Hz, IH), 7.0 it, 0=3 Hz, 2H), 3.9 (s, 3H), 3.85 (m, 2H), 3.0 (t, J=7 Hz, 2H);
MS (FD) m/e 324 (M+);
UV (EtOH) 269nm (£=16845), 235 nm (£=10636), 201 nm (£=16622) .
Example 339
N-.12-.2-Pvr:d:-'-i..eth·,·! ] -Ν' - f 3.-16-chlcro pyridazinyl)
Lhlpur.ea
A solution of 1,1'-thiocarbonyldiimidazole (1.83 g, 10.0 mmol) and 3-amino-6-chloro pyridazine (1.3 g, 10.0 mmol) in acetonitrile (100 mL) was stirred at room temperature for 288 h. To this solution was added 2- (2aminoethyl) pyridine (1.22 g, 10 mmol) and the resultant mixture stirred at room temperature for 48 h. The solvent was removed in vacuo and the residue purified by HPLC to provide 0.300 g (10.0%) of the titled product:
mp 197-199‘C;
R (KBr, cm’1) 3172, 3045, 1583, 1562, 1511, 1478, 1428,
K7
CU >>
o o
un o
Cl
CL <
1345,1313, 1230 ; NMR (3 00 MHz, DMSO-dg) δ 11.3 (m, IH), 10.9 (s, IH), 8.6
(d, J=5 Hz, IK), 7.8 (d, J=10 Hz, IH), 7.7 (m, IH) , 7.55
(d, J=10 Hz, IH) , 7.3 (d, J=8 Hz, IH), 7.2 (m, IK) , 4.0 (m,
2H) , 3.1 (t, J=7 Hz, 2H);
MS (FD) m/e 293 (M+) ;
pka '66% DMF) is 4.17, 12.32;
UV (EtOH) 275nm (£=21715), 270 nm (ε=218 3 6) , 221 nm (£=9867 ) .
BAD ORIGINAL d
AP Ο Ο Ο 3 8 β
-268Anal. Calcd for C12H12N5SCI2: C, 49.06; Η, 4.12; Ν. 23.84. Found: C, 48.91; Η, 4.14; Ν, 23.76.
Example 34.Q
N-.-f..2z.l2^..6r.Dif.luorophenyl: ethyl! -Ν' - (2- f5-bromo)pyridyll rhiourea
A stirred solution of N-(thioimidazoyl)-2(2,6-difluorophenyl) ethyl amine (2.67 g, 10 mmol) and 2amino-5-bromopyridine (1.73 g, 10 mmol) in 1-methyl-210 pyrrolidinone (20 mL) was heated to 90’c. After 16.5 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with H20 (2x), IN HCi, H2O and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The solid obtained was purified by recrystallization from 1:1
EtOAc/hexanes to provide 1.6 g (43%) of the titled product. This material was recrystallized again from 70% EtOAc/hexanes to provide 1.16 g of the titled product as a light brown crystalline solid:
mp 174-175°C;
IR (KBr, cm*1) 3229, 1593, 1558, 1529, 1468, 1265, 1188, 1071, 832;
NMR (300 MHZ, DMSO-dg) δ 11.20 (s, IH), 10.68 (s, IH) ,
8.11 (s', IH), 7.95-7.91 (m, IH) , 7.33-7.28 (m, IH) , 7.0925 7.01 (m, 3H), 3.83-3.77 (m, 2H), 2.98-2.94 tin, 2H) ;
MS (FD) m/e 371 (M+), 373 !M*2);
UV (EtOH) 306nm (£=127 90) , 275nm (£=22096) , 257nm (£=14120), 2Clnm (£=17270) .
Anal. Calcd for Ci4Hi2BrF2N3S: C, 45.17; H,
3,25; N, 11.29. Found: C, 44.96; H, 3.29; N, 11.21.
AP/P/ 9 5 / 0 0 7 2 3 bad ORIGINAL
AP Ο Ο Ο 3 8 8
-269Examsle 24,1
2.z-£y-ancm.e.thyl.-2 -e:h??g/Eyr;dine A solution of thionyl chloride (3.26 g, 27.4 mmol, 2.0 mL, in CH2CI2 (10 mL) was added dropwise with 5 stirring to a solution of 2-ethoxy-3hydroxymethylpyridine (3.0 g, 19.6 mmol) in CH2CI2 (20 mL) at 0°C. The ice bath was removed and the reaction stirred 2 h at RT. The reaction was concentrated in vacuo and redissolved in MeOH (30 mL,. Potassium cyanide (3.82 g, 58.7 mmol) was dissolved in K£0 (10 mL) and added to the reaction in one amount. The reaction was heated to reflux and stirred for 66 h, then quenched with saturated Na2CO3 solution. The reaction was diluted with H2O and extracted with Et2° f3x). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated to yield 2.84 g (89%) of the titled product as a brownish oil. A small sample was further purified by flash chromatography (40% EtOAc/hexanes) to provide a clear, colorless oil:
IR (KBr, cm'1) 3020, 2988, 2936, 1579, 1450, 1397, 1282, 1122, 1041;
!h NMR (300 MHZ, CDCI3) δ 8.17-8.15 (m, IH) , 7.25-7.15 (m, 2H), 4.09 (q, J=7 Hz, 2H), 3.90 (s, 2H), 1.47 (t, J=7 Hz, 3H) ;
MS (FD) m/e 162 (M+) ;
UV (EtOH) 278nm (ε= 5241), 220nm (ε= 7490).
Cx cr cr u~
a.
£ <
APO00388
-270Example 342
Ν- Γ2- (3-ethcxvsyridvl).ethvll -Ν' - f 2- (5-bromo) pyr idyll thiaurea
A solution of 2-cyanomethyl-3-ethoxypyridine 5 (22.03 g, 136 mmol) in EtOH (475 mL) and 5N HCl (3 mL) was treated with PtO2 catalyst (4.5 g) under 60 psi of H2. The reaction was stirred overnight at RT, then filtered. The crude reaction was concentrated and redissolved in H2O and EtOAc. The aqueous layer was made basic with 5N NaOH and extracted with EtOAc. The organic layer was washed with brine, dried on Na2SO4, filtered and concentrated to give 16.89 g of a yellow oil. This crude product was dissolved in 1-methyl-2-pyrrolidinone (175 mL) and N- (thioimidazoyl)-2-amino-5-bromopyridine (36 g, 127 mmol) was added. The reaction was heated to
100°C and stirred for 68 h. The crude reaction was cooled and poured into EtOAc. The organic layer was washed with H2O (4x), brine, dried on Na2SO4, filtered and concentrated. The resulting solid was again dissolved in EtOAc and extracted with IN HCl (3x). The acid extracts were stirred with CH2CI2, made basic with 5N NaOH and extracted with CH2CI2 (2x). The CH2CI2 extracts were combined, washed with brine, dried on MgSO4, filtered and concentrated. The crude product was purified by flash chromatography (10% EtOAc/CH2Cl2), followed by trituration with 1:1 EtCAc/hexanes to provide 3.76 g of the titled product (7%) as a white crystalline solid :
mp 170-172°C;
2H NMR (3 00 MHZ, DMSC-C?g) 6 11.39 (s, IH) , 10.59 (s, IH) ,
8.13-8.11 (m, 2H>, 7.92-7.87 (m, IH), 7.30 (d, J=8.1 Hz,
AP/P/ 9 5 / 0 0 7 2 3
BAD ORIGINAL
AP Ο Ο Ο 3 8 8
-271IH) , 7.22-7.18 (m, 1Η), 7.05 id, J=8.9 Hz, IH) , 4.05-3.95 (m, 4Η), 3.00 (t, 0=6.3 Hz, 2H) , 1.23 ic, 0=6.9 Hz, 3HI; MS (FD) m/e 3S0 (M+), 382 (M+2);
UV (EtOH) 3C5nm (ε= 16291), 276nm (€= 36829).
Example 343
N---L2r.i3.-gthaxYpyridvl) ethvll -Ν' - f2-.(5-trcmc(pyridvl1 thiourea hydrochloride
N-I 2-¢3-ethoxypyridyl) ethyl]-N'-t2-(5bromo)pyridyl] thiourea (5.17 g, 13.5 rrmol! was dissolved in a saturated solution of methanolic HCl (100 mL) with stirring. After complete dissolution, a precipitate started to form. The solution was poured into Et2O (400 mL) with stirring, and the resulting white solid was filtered. The crude product was triturated with 10% MeOK/EtOAc to provide 5.47 g of the titled product (97%) as a white solid;
mp 203-205°C (d) ;
IR (KBr, cm*1) 3226, 3007, 2306, 1593, 1565, 1530, 1472,
1290, 1197, 1172;
NMR (300 MHZ, DMSO-dg) δ 11.24-11.20 (m, IK), 10.65 (s.
IH), 8.29 (d, 0=5.3 Hz, IH), 8.17 id, J=2.3 Hz, IH),
7.96-7.88 (m, 2H), 7.73 -7.68 (m, 2H), 7.08 id, 0 = 8.9 Hz,
IH), 4.10- 4.03 (m, 4H), 3.24 ft, 0=6.9 Hz, 2K), 1.27 (t,
0=6.9 Hz, 3H) ;
AP/P/ 9 5/0^723
MS (FD) m/e 380 (M+), 382 (M+2);
UV (EtOH) 304nm (€=13635) , 276nm (€=28376 ) .
Anal. Calcd for CicHigBrClI^OS; C, 43.13; H, 4.34; N, 13.41. Found: C, 42.90; H, 4.36; N, 13.11.
BAD ORIGINAL a
AP Ο Ο Ο 3 8 8
-212Sxaspls- 344 l-f (2-amir.orS.-bromopyridyl) thiocarbamovΠ imidazole
A solution of 1,1'-thiocarbonyldiimidazole (17.8G, O.lm) and 2-amino-5-bromopyridine -17.3g, 0.1m) in acetonitrile (150 mL) was stirred at room temperature for 2 hours. To this suspension was added the material described below.
Example 345 N-f2-(2-pvridvl) ethvU ImN.'..-(2-amino-5-bromopvridv:) thiourea
To the above solution of 1brcmopyridyl)thiocarbamoylJ imidazole aminoethyl/pyridine (14.7g, 0.12m) st hours and at 50 C 12 hours. The react room temperature, filtered, washed wi The resultant solid was dissolved in hydrogen chloride gas was bubbled int cooling. Solvents removed under reduc resulting residue was recrystallized ether to provide 24.6g (76%) of the t white solid:
mp 215-216 C;
IR (KBr, cm4) 3015, 2576, 1634, mult (1633-400) ;
1H NMR (300 MHz, DMSC-dg) δ 11.30 (s, 10.78 (s,lH), 8.80 (d, IH), 8.40 (t, 7.97-8.00 (q, IH) , 7.S2-7.90(d, IH) , ' (d, IH), 4.10(q,2H), 3.35(t, 2H) ;
MS (FD) m/e 338(M+);
•' .2-amino-5was added 2-(2irred at r.t. for 2 ion was cooled to th acetonitrile, methanol, filtered, o this solution with ed pressure and the from methanol ethyl itled product as a iple peaks between
IH), 10.75 (s, IH), , 8.22 (s, ih) ,
7.50(t, 1H), 7.10
AP/P/ 9 5 / 0 0 7 2 3
BAD ORIGINAL
AP Ο Ο Ο 3 8 8
-273UV (EtOH) 3O5nm (£=13565), 274nm (ε=242Ο1), 201 nm (£=17628) .
Anal. Calcd fcr Cl3Hi4N4BrClS: C, 41.78; H, 3.78; N, 14.99. Found: C, 42.02; H, 3.86; N, 15.16.
Example 346
N-F2- ( (3-Methoxv)_pyridvP ethyl1 - r2- (5brcmc'pvridvlιthiourea .hydrochloride
A) Preparation cf 2-Hvdroxvmethvl-3-methcxv pvrldine.
Potassium hydroxide (41.66g ,0.744 mol) was ground under nitrogen and stirred in DMSO <130 ml, anhydrous) for 20 min. 3-Hydroxy-2-hydroxymethyl pyridine hydrochloride [Aldrich] (47 g, 0.248 mol) was added and stirred for 30 min in an ice bath. Methyl iodide (35.2 g, 0.248 mol, 15.43 ml) in DMSO (20 ml) was added dropwise to the solution and then allowed to stir overnight at room temperature. 5N HCl was added to pH 1 and the solution was extracted with dichloromethane (5X
500ml). The aqueous was then basified with 5N NaOH to pH and extracted with dichloromethane (3X 500 ml). The organics (base wash) were dried over sodium sulfate, and concentrated leaving tan colored crystals. The solid was recrystallized (50% ethyl acetate/hexanes) providing 1C. 8 g (32%) of the titled product as light tan crystals: mp 7 2 °C;
IR (KBr', cm-1) 3QS0, 1575, 1459, 1424, 1278, 1218, 1066, 809 ;
AP/P/ 9 5 / 0 0 7 2 3
BAD ORIGINAL &
AP Ο Ο Ο 3 8 8
-2743Η NMR (3OC MHZ, DMSO-dg) δ 8.5 (d,J=4.5Ηζ,1Η), 7.3 (ά,J=8.3Hz,1Η), 7.25 (dd,J=8.2,4.6 Hz,1Η), 4.77 (t,J=5.74Kz,IH), 4.48 (d,J=5.6Ηζ,2Η), 3.77 (s,3H);
MS (FD) m/e 139 (M+);
UV (EtCH) 278nm (£=4909) , 220nm (£=6984 ) .
Anal. Calcd for C7H5NO2: C,60.42; H,6.52; N,10.07.
Found: C, 60.32; H.6.54; N,10.23.
B) Preparation of 2-f (3-methoxv)pvridvl1acetcnitrile.
Thionylchloride (100 ml) was added dropwise to
2-Hydroxymethyl-3-methoxy pyridine (13.9 g, 0.1 mol) while stirring in an ice bath. After initial fuming subsided, the thionyl chloride was added more rapidly.
The solution was then heated to reflux for 2 h. After cooling, the thionyl chloride was removed under reduced pressure leaving brown crystals. The solid was taken up in 190 ml methanol and potassium cyanide (19.4 g, 0.298 mol) dissolved in 80 ml of water was added to the methanolic solution. This solution was heated to reflux and allowed to reflux overnight. The solution was cooled down and 150 ml of saturated sodium carbonate was added and then poured into diethyl ether (500 ml). The solution was extracted 3 more times with 500 ml diethyl ether. The collected organics were washed with brine and saturated sodium bicarbonate. The organics were dried over sodium sulfate and concentrated giving 12.1 g (81.7%) of brown crystalline solid. This solid was used in the reduction without further purification: mp 71°C;
AP/P' 9 5 / 0 0 7 2 3
BAD ORIGINAL &
APO00388
-275IR (KSr, err.1) 30^4, 2949, 2253, 1578, 1459, 1286, 1017, 821;
1H NMR (300 MHZ, DMSO-dg) δ 8.07 (m,IH), 7.43 (m,lH), 7.35 im,lH), 4.0 (s,2H), 3.8 (s,3H);
MS (FD) m/e 148(M+5;
UV (EtOH) 278nm (£=5407), 219nm (£=7435) .
Anal. Calcd for C3HON2O: 0,64.85; H,5.44; N,18.91 . Found: C, 64.62; H,5.50; N,19.0.
C) Preparation c: l-Ethvlamine-B-methoxypyridine.
2-[ (3-methoxy'pyridyl]acetonitrile (2.0 g, 13 mmol) in 2 5 ml ethanol was reduced at room temperature under 60 p.s.i. for 24 h using platinum oxide (0.5 g) and 5N HCl (0.2 ml) as catalyst. The organics were concentrated and then taken up in ethyl acetate and water. IN NaOH was added to pH 12 and the amine was extracted out (2x300 ml ethyl acetate). The organics were then washed with brine and saturated sodium bicarbonate and then dried over sodium sulfate. The solution is filtered and concentrated giving 1.5 g of oily material. This is used without further purification.
D) Preparation of N-; 2-((3-Methoxy)pvridvl) ethvl]-Ν’- Γ225 (5-bromo)pvridvlI thiourea
Thiocarbonyldiimidazole (5 g, 28 mmol) was taken up in acetonitrile (50 ml, anhydrous) and stirred. 2-Amino-5-bromopyridine [Aldrich] (4.85 g, 28 mmol) and 30 ml acetonitrile was added to the solution. The κ
rc
LT σ
a a
AP Ο Ο Ο 3 8 8
-276precipitate. The cream colored solid was filtered off and used in the next reaction without further purification. (6.89 g, 87%)
The cream colored solid (2.88 g, 10.3 mmol) was taken up in l-methyl-2-pyrrolidinone [Aldrich], 2Ethylamine-3-methoxypyridine was added and the solution was heated to 100°C overnight. The solution was poured into ethyl acetate and washed with water and saturated sodium bicarbonate (3x 200 ml) . The organics were then dried over sodium sulfate and concentrated. The crude material was purified by flash chromatography on silica gel using 40% ethyl acetate /hexanes, giving lOOmg (3%) of needle-like crystals:
mp 17 8°C;
IR (KBr, cm1) 3157, 3037, 1595, 1562, 1534, 1314, 1275, 1178, 1023, 825;
!h NMR (300 MHZ, DMSO-dg) 511.53 (S,1H), 8.5 (s,lH), 8.17-8.12 (m,2H), 7.68-7.65 (dd, J=8.75, 8.73Hz, IH), 4.24-4.18 (m,2H), 3.8 (s,3H), 3.2-3.17 (t, J=6.63Hz, 2H);
MS (FD) m/e 366 (M+) , 368(M+l),369 (M+2) ;
UV (EtOH) 305nm (£=13005), 275nm (£=28998) .
Anal. Calcd for Ci4Hi5N4OS3r: C,45.78; H,4.12; N,15.25 . Found: C,45.85; H.4.12; N, 15.12.
E) Preparation of N-J2-((3-Methoxv)Pvridvl)ethvIl-N,-f2(5-bromo?pvridvl]thiourea hydrochloride
N-[2-((3-Methoxy)pyridyl)ethyl]-N’-[2-(5bromo)pyridyl]thiourea (70 mg, 0.02 mmol) was taken up in a solution of methanol saturated with HCl. The solid immediately went into solution and then came back out as a white solid. More of the solid was crashed out with
AP/P/ 9 5 / 0 0 7 2 3
BAD ORIGINAL
AP Ο Ο Ο 3 8 8
-277diethyl ether. This solid was filtered providing 65 mg (84%) of the hydrochloride salt.
Example 347
N- (2- (2-Fluoro-6-methoxv)_-ch&nethvl) -Ν' - (2-thiazolvl) thlaursa
3-Fluoro-anisole (10 ml. 88 mmol) was dissolved in dry THF (200 ml). The solution was cooled to -75° C and n-BuLi (52 ml, 105 mmol) was added slowly. The pale yellow solution was stirred at -70°C for 10 minutes. DMF (20 ml) was added and the solution was warmed to ambient temperature. Toluene (200 ml) was added and the solution was washed with water and evaporated to dryness. The product formed crystals. The aldehyde was transformed into the corresponding titled thiazolyl-thiourea product according to the procedure in Example 151.
1H NMR,CDCl3 δ 2.9-3.0 (2H, t) 3.7-3.9 (2H, t) 6.7-6.9 (2H, q, m) 7-7.1 (IH, d,) 7.15-7.3 (IH, q) 7.4 (IH,
d) .
Example 348
Cis-(D.L)-2-phenvlevelopropvlamine Styrene (100 ml, 873 mmol), Cul (10 mg, 0.05 mmcl) and Pd(OAc)2 (10 mg, 0.045 mmol) in 1,225 dichloroethane (100 ml) was heated to reflux. Ethyl diazoacetate (50 ml, 475 mmol) in styrene (100 ml, 873 mmol) was added over 30 minutes. The solution was refluxed for an additional 5 minutes. The solution was cooled and filtered through a short column of alumina which was eluted with ethyl acetate/hexane
AP/P/ 9 5 / 0 0 7 2 3
BAD ORIGINAL rf
AP 0 Ο Ο 3 8 8
-278(1:9). The solvents including styrene were evaporated. The residual oil contained a cis-trans mixture (3:7). The oil was dissolved in methanol (200 ml), and potassium hydroxide (30 g, 535 mmol) in water (50 ml) was added. The solution was refluxed for 2 hours. The solution was cooled and diluted with toluene (100 ml) and water (100 ml).
The water-phase was separated and acidified with hydrochloric acid. The solution was extracted with toluene. The organic phase was dried with sodium sulphate, filtered and evaporated, yielding a pale brown solid. The solid (70 g, 430 mmol) was dissolved in acetone (400 ml) with mechanical stirring under an atmosphere of N2-gas. Triethylamine (70 ml, 502 mmol) was added. The solution was cooled to 5° C and ethyl chloroformate (41 ml, 430 mmol) was added during 20 minutes. The solution was stirred for an additional 5 minutes. Sodium azide (30 g, 460 mmol) in water (100 ml) was added and the solution was stirred for 30 minutes. Toluene (400 ml) was added and a thick, white precipitate formed. The solution was decanted to remove the precipitate and dried with sodium sulphate (50 g). The solution was evaporated to 1/4 of the original volume. The solution was diluted with
1,2-dichloro-ethane (400 ml) and was refluxed for 3 hours with evolution of nitrogen gas.
To the solution was added a mixture of
AP/P/ 9 5 / 0 0 7 2 3 hydrochloric acid (cone. aq.) (100 ml), water (100 ml) and dioxane (200 ml) . The solution was refluxed for 3 hours with evolution of CO2 gas. The solution was
AP Ο Ο Ο 3 β 8
-279separated and washed with 1,2-dichloroethane, basified with ammonia (cone, aq.) and extracted with dichloromethane (3 x 100 ml). The organic-phase was washed with water (ICC ml), dried with sodium5 sulphate, filtered and evaporated.
g of the residual oil was separated on
1000 ml silica-gel, by elution with ethyl acetate, the product (cis) is the faster-eluting component. The pure cis-fractions were evaporated to yield an oil
Ϊ'? (14g).
-H-NMR CDCI3 5ppm 0.8-0.9 (1H, CH2 , m) 1.1-1.2 (1H, CH2. m; 2.-2.1 (1H, PhCH, q) 2.6-2.7 (1H, CHNH2m.) 7.1-7.4 (5H, Ph.).
-j Example 349
N---icis- (D.L1 -2rPhenvlcyclQDr.ppyl) -N/.- (2-thiazolvl) thiourea
The product cis-(D,L)-2phenylcyclopropylamine from Example 348 was transformed into the titled product according to the procedure in Example 151.
1H-NMP. CDC13 δ ppm 1.2-1.3 (1H, CH2, m) 1.5-1.6 (1H, m! 2.4-2.5 (1H, q, PhCH) 3.6-3.7 (1H, m) 6.6-6.7 (1H, d)
6.8-6.9 CH, d) 7.2-7.4 (5H, m)
Example 35P
N-(cis- (P,L)-2-phenvlcvclobutvl)-Ν' -(2-thiazolvl) thiourea
A cis/trans mixture of 2phenylcyclobutylamdne (C. Beard, A. Burger, JOC, 27,
AP/P/ 9 5 / 0 0 7 2 3 bad original A
AP Ο Ο Ο 3 8 8
-2801647 (1962)) (0.150 g, 1 mmol) was condensed with 165 mg of the product of Example 103 according to the procedure of Example 105. The solution was put into a refrigerator (-10°C, over night and the crystals were collected on a filter and washed with CH3CN. The stereochemistry was determined with NOE-difference NMR. The crystals were pure cis.
^-H-NMR CDCI3 5ppm 2.2-2.4 (3H, m) 2.6-2.7 (IH, m) 3.9-4.0 (IH, q) 5.1-5.2 (IH, q) 6.6-6.7 (IH, d, thiazole) 6.8-6.9 (IH, d, thiazole) 7.3-7.5 (5H, m.
Ph) .
Example 351
R^Lcisr (D·,!,) -2-jnethvl-2-phenvl-cyclopropvl) -Ν' - (415 chloropheaylIthiourea a-Methylstyrene (Aldrich) was transformed into the corresponding amine as a cis-trans mixture according to the procedure of Example 348. The amine (300 mg', 2.04 mmol) and 4-chloro-phenylisothiocyanate
2C were refluxed in CH3CN (5 ml) for 60 minutes. The solution was evaporated and final purification was made by flash-chromatography on silica-gel by elution with ethyl acetate/n-hexane (1:4). The collected fractions were pure cis as determined by NOE25 difference NMR.
XH-NMR CDCI3 δΐ.1-1.2 (2H, m, CH2> 1.4-1.5 <3H, s, CH3), 3.2-3.4 (IH, m, CflN), 6.4-6.5 (IH, b.s., NH), 7.0-7.1 (2H, Ph), 7.3-7.5 (7H, s,+m, Ph). 7.9-8.1 (IH, b.s., NH)·
AP/P/ 95/00723
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AP Ο Ο Ο 3 8 8
-281Sxample 2,52
Ν-(2-(2.6-difluorophenyl)ethvl)-Ν' -(2-pvrazinvl)thiourea
2.6- Difluorophenethylamine (1.0 g, 6.4 mmcl), 2-aminopyrazine (0.61 g, 6.4 mmol) and N,Nthiccarbonyl-diimidazole (1.13 g, 6.4 mmol) were condensed according to the procedure of Example 93 to give the titled compound as crystals.
1H-NMR CDCI3 6ppm 3.1-3.2 (2H, t, PhCH2)' 3.9-4.0 10 (2H, t, CH2N),
6.8-6.9 (2H, t, Ph), 7.1-7.3 (IH, m. Ph), 7.9-8.0 (IH, s, pyr), 8.1-8.2 (IH, d, pyr), 8.3-8.4 (IH, s, pyr), 9.3-9.4 (IH, b.s., NH) , 11.0-11.2 (IH, b.s.,
NH) .
Example 353
H-(2-(2,6-difluoro-3-carboxamidomethvl phenvl)ethvl) N* - i2- (5-brpmocyrldyl)..-thiourea
2.6- Difluorobenzaldehyde (10 g, 70.4 mmol), ethylene glycol (20 ml), triethyl-orthoformate (10 ml) and para-toluene sulphonic acid in 1,2-dichloroethane were heated to 80°C for 2 hours. The solution was neutralized with sodium hydrogen carbonate, washed with water, dried with sodium sulfate, filtered and evaporated. The residual oil was dissolved in tetrahydrofurane (700 ml) under nitrogen-atmosphere. The solution was stirred and cooled to -70°C and nBuLi (48ml, 1.6 M) was added slowly. The solution was stirred for 20 minutes. Dry-ice (20 g, 455 mmol) was £ I L U U / S 6 /a/atf
AP Ο Ο Ο 3 8 β
-282T'ne solution was slowly brought up to ambient temperature. Water was added and the solution was washed with ethyl acetate, acidified with acetic acid and extracted with ethyl acetate.
The organic phase was dried with sodium sulfate, filtered and evaporated. 1 g of the residual solid (4.35 mmol) and Ν,Ν-diisopropylamine (2.0 ml) were dissolved in dichloromethane (50 ml) and the solution was cooled to 0°C.
Thionylchloride (0.50 ml, 6.9 mmol) was added and the solution was slowly heated to ambient temperature. Methylamine (3 ml) was added. The solution was stirred for 30 minutes and was washed with water, dried with sodium sulfate, filtered and evaporated.
The residue was dissolved in a mixture of water and dioxane (1:2, 20 ml) and para-toluene sulphonic acid (0.5 g, 2.63 mmol) was added. The solution was stirred and heated to 60°C for 2 hours.
The solution was neutralized with sodium hydrogen carbonate, extracted with ethyl acetate, dried with sodium sulfate, filtered and evaporated.
The residue was dissolved in toluene and benzyl oxy carbony lmethyl triphenyl-phosphorane (1.5 g,
3.7 g) was added. The solution was stirred for 30 minutes at 50°C. The solution was put onto a silicagel column. The column was eluted with ethyl acetatehexane (1:2) and the collected fractions were evaporated. 0.15 g of the residue was hydrogenated in methanol (50 ml) and acetic acid (5 ml) with Pd/C (10
AP/P/ 95/00723 bad original
APO 00 388
-283%, 100 mg) and hydrogen gas, using a Parr apparatus at 1.5 bar for 1 hour.
The solution was filtered through Celite and evaporated. A part of the residue (50 mg, 0.26 mmol) was dissolved in acetone at 0°C.
Triethylamine (50 ml, 0.36 mmol) was added followed by ethyl chloroformate (30 ml, 0.32 mmol).
The solution was stirred for 15 minutes and sodium azide (30 mg, 0.46 mmol) in water (2 ml) was added.
The solution was stirred for 15 minutes, diluted with ethyl acetate, washed with water, dried with sodium sulfate, filtered and evaporated.
The residue was dissolved in toluene (20 ml) and was stirred and heated at 90° C for 1 hour. The solution was evaporated and dissolved in a dioxanewater-hydrochloric acid (cone. aq.) mixture (1:3:1).
The solution was stirred at ambient temperature for 20 minutes. The solution was evaporated and the residual 2- (2,6-dif luoro-3-carboxami domethyl pheny 1) ethylamine hydrochloride was condensed with l-(2-amino-5bromopyridyl)-11 -(imidazolyl) thiocarbonyl using the procedure of Example 94.
The reaction mixture was evaporated and the residue was purified by flash chromatography on silica-gel by elution with ethyl acetate-hexane (1:1). Evaporation of the collected fractions yielded the titled product.
CPC] ; δ ppm 2.9-3.0 (3h, γ. , CH3), 3.)-3.2 (2H, t, PhCH2), 4.0-4.1 (2H, t, CH2N), 6.8-6.9 (IH, d) , 6.9-7.0 (2H, t), 7.7-7.8 (2H, m), 8.0-8.1 (IH, s) .
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AP000388
-284Example 354
N-(2- (3-acetamidomethvl-2,6-difluorophenyl)-ethvl)-N'(2 - i5-brQmpE?yxidyl)J - thiourea 5 Under an atmosphere of nitrogen-gas, 2,4difluorobenzonitrile (Aldrich) (4.6 g, 33 mmol) was dissolved in tetrahydrofurane (200 ml) with stirring under an atmosphere of nitrogen gas. The solution was cooled to -75°C and lithium-diisopropylamide (25 ml,
1.5 M solution) was added. The solution was stirred for 15 minutes and dimethylformamide (10 ml) was added. The cooling was withdrawn and the solution was diluted with toluene (200 ml), washed with water, dried with sodium sulfate, filtered and evaporated.
The residue (4.76 g, 28.5 mmol) was dissolved in 250 ml toluene and benzyloxycarbony Imethyl triphenylphosphorane (14 g, 34 mmol) was added.
The solution was stirred for 40 minutes at 35°C (slightly exothermic reaction), and then put onto a column of silica gel. The column was eluted with ethyl acetate-hexane 1:4, and the collected fractions were evaporated. A small part of the residue (0.5 g) was dissolved in methanol (50 ml) and acetic acid (6 ml) and 5 % - Pd/C (300 mg) was added. The mixture was hydrogenated in a Parr apparatus at 1.5 bar for 1 hour.
The solution was filtered through celite and evupiudLeJ, The residue was dissolved in acetic anhydride and the solution was stirred and heated to
50°C for 20 minutes. Excess reagent was evaporated
AP/P/ 95/00723 bad ORIGINAL
AP Ο Ο Ο 3 8 8
-285and the residue was dissolved in water. The solution was heated to 60° C for 20 minutes under stirring. The residue (0.29 g, 1.14 mmol) was dissolved in acetone at 0°C.
Triethylamine (0.315 ml, 2.3 mmol) was added, followed by ethyl chloroformate (0.16 ml, 1.7 mmol). The solution was stirred for 15 minutes and sodium azide (220 mg, 3.3 mmol) in water (2 ml) was added. The solution was stirred for 15 minutes, diluted with ethyl acetate, washed with water, dried with sodium sulfate, filtered and evaporated.
The residue was dissolved in toluene (20 ml) and was stirred and heated at 90°C for 1 hour. The solution was evaporated and dissolved in a dioxane15 water-hydrochloric acid (cone, aq.) mixture (50:10:1, ml). The solution was stirred at ambient temperature for 20 minutes. The solution was evaporated and the residual amine-hydrochloride was condensed with 1-(2-amino-5-bromopyridyl)-1'20 (imidazolyl) thiocarbonyl using the procedure of
Example 94.
The reaction-mixture was evaporated and the residue was purified by flash chromatography on silica-gel by elution with ethyl acetate-hexane (1-.1).
The collected fractions were evaporated to yield the titled product as crystals.
1H-NMR CDCI3 5ppm 1.9-2.0 (3H, s, CH3CON), 3.0-3.1 .;2H. h.s., PhCUjCHgN) , 3.9-4.1 (2H, b.s.. rhClbCHgN) , 4.3-4.4 (2H, s, PhCH2N), 6.8-6.9 (2H, m> , 7.2-7.4 (IH,
m). 7.7-7.8 (IH, d), 8.1-8.2 (IH, s).
M*IPf 95/00723
ORIGINAL A
ΑΡ 0 0 0 3 8 8
-286Exampla J.5.5,
Ν-(4-methvl-3-pentenvl)-Ν'-(4-methvl-2thiazglYllxhiourea
4-Methyl-3-pentenylamine and an activated derivative of 2-amino-4-methylthiazole, i.e. 1-(2amino-4-methylthiazole)-1'-imidazole thiocarbonyl, were condensed according to the procedures of Example 105 to give the titled product.
Mp.: 164.5 - 165.5°C.
Analyses: Calculated C 51.73, H 6.71, N 16.45; Found C 52.0, H 6.9, N 16.7.
iH-NMR (CDCI3 d): 1.65 (s, 3H) , 1.73 (d, 3H), 2.29 (d, 3H), 2.40 (q, 2H), 3.70-3.78 (m, 2H) , 5.16-5.22 (m,
IH), 6.36 (q, IH), 10.14 (broad s, IH), 10.90 (broad s, IH).
13C NMR (CDCl3d): 17.16, 17.93, 25.83, 27.28, 45.69, 105.04, 120.53, 134.84, 147.99, 160.79, 177.28.
Example 356
N-(2-(2, .6-dif luoro)-phenethyl)-Ν’ -(2benzimidazolyl) thiourea
2,6-Difluorphenetylamine and 2aminobenzimidazole were reacted according to the procedures of Examples 93 and 94, using 2aminobenzimidazole instead of 2-aminothiazole, to give the titled product.
Mp: 1Q5-7°C (dec) 1H-NMR (DMSO-dg d): 3.16 (t, 2H), 4.02 (q, 2H), 7.1430 7.24 (m, 4H), 7.43-7.49 (m, 3H), 11.13 (broad s, IH),
11.40 (broad s, IH).
AP/P/ 95/0072 3
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-287Example 357
N-(2-(3-hvdroxy) -phenethyl 1-Ν' - (5-bromo-2pYridinvl.llhipurea
3-Hydroxyphenethylamine and 5-bromo-2aminopyridine were reacted according to the procedures of Examples 93 and 94, using 4-bromo-2-aminopyridine instead of 2-aminothiazole, to give the titled product..
Yield: 35 %.
Mp: 176.5 - 178.0°C.
iH-NMR (DMSO-dg d,: 2.95 (t, 2H), 3.90 (q. 2H), 6.736.85 (m, 3H), 7.20-7.27 (m, 2H), 8.08 (dd, IH,, 8.32 (d, IH), 9.49 (s, IH), 10.84 (s, H, , 11.33 (t, IH) .
13C-NMR (DMSO-dg d): 34.01, 46.30, 111.70, 113.26, 114.41, 115.70, 119.32, 129.35, 140.41, 141.29,
145.79, 152.29, 157.34, 179.07.
Examp 15.,3..5 8
N-(2-(1-methvl)-2-pvrrolvlethvl)-Ν' -(5-chloio-2pvridinvl) thiourea
2-(Aminoethyl)-1-methylpyrrole and an isothiocyanate of 5-chloro-2-aminopyridine were condensed analogous to the procedures described in
Example 105, to give the titled product.
Yield: 78 %.
Mp: 169.5-170.0°C.
1h-NMF. (DMSO-dg d): 3.01 (t, 2H) , 3.67 (s, 3H) , 3.93 (q, 2H), 6.00 - 6.02 (m, 2H), 6.74 (s, IH), 7.32 (d,
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-2881Η), 7.97 (dd, 1Η) , 8.27 (d, 1Η), 10.76 (s, 1Η), 11.36 (broad s, IH).
13C-NMP. (DMSO-dg d) : 24.97, 33.19, 44.37, 106.22,
106.39, 114.02, 121.58, 123.70, 129.32, 138.70,
143.61, 152.05, 179.31.
Example.353
H-.( 2-(3 -Methyl) phenethyl), -N ‘ (2-thiazolyl) thiouroa (3-Methyl-phenyl)acetic acid was reduced 10 with lithium aluminum hydride in tetrahydrofurane under reflux to 2-(3-methyl-phenyl)ethanol, which was further transformed to 2-(3-methyl-phenyl)ethylamine by the procedure described in Example 106.
Condensation of this amine with the product of Example 15 103 and using the procedure described in Example 105, gave the titled product.
13C-NMR (250MHz, CDC13): 5178, 162, 138, 137, 137,
130, 128, 127, 126, 102, 47, 35, 22.
Mp: 145 - 146°C.
Example 360
N-J.2-T (2-Ethoxv)Dhenethvl) -Ν' -(2-(4methyl J thiazolyl) thiourea
In a manner analogous to Example 105, 2-(225 ethoxyphenyl)ethylamine was condensed with l-(2-amino4-methylthiazoly1)-1'- imidazole thiocarbonyl, which was made in a similar way as described in Example 103, to give the titled product.
iH-NMR (250 MHz, DMSO): 67.32 - 6.73 (m, 5H, phenyl, thiazole), 4.09 (q, 2H, OCH2CH3), 3.86 (q, 2H, CH2NH),_ bad ORIGINAL
AP Ο Ο Ο 3 8 8
-2892.97 (t, 2Η, Ph-Ch2), 2.25 (s, 3Η, thiazole-CH3), 1.43 (t, 3Η, OCH2CH3)· 13C-NMR (250 MHz, DMSO): δ176, 162, 157, 130, 128,
127, 120, 112, 107, 106, 63, 44, 29, 17, 15.
Mp: 188 - 189°C.
Example 361
N- ¢2-(3-Ethoxv)Phenethvl)-N1-(2-thiazolyl)thiourea
3-Hydroxybenzaldehyde (3.0 g, 24.6 mmol), ethyl iodide (5.9 ml, 73.8 mmol) and K2CO3 (3.4 g,
24.6 mmol) in 50 ml of acetone was stirred at +40°C for 6 h and at RT overnight. The mixture was filtered 3nd evaporated. The product was purified by silica gel column chromatography (EtOAc/petroleum ether
15:100) to give 3-ethoxybenzaldehyde.
Yield 2.91 g (79%).
1H-NMR (250 MHz, CDCI3): 9.97 (s, IH, CHO), 7.45 7.14 (m, 4H, phenyl), 4.10 (q, 2H, CH2CH3), 1.44 (t,
3H, CH2CH3).
By using the procedure of Example 151, 3ethcxybenzaldehyde was transformed to 2-(3ethoxyphenyl)ethylamine, which was reacted with the product of Example 103, following the procedure of
Example 105 to give the titled product.
!h-NMR (250 MHz, DMSO): δ7.60 (d, IH, thiazole), 7.30 - 6.93 (m, 4H, phenyl), 4.08 (q, 2H, OCH2CH3), 3.87 (q, 2!I, CH2-NH>, 2.96 (L, 2H, phenyl-CH2), 1.42 (t,
3H, OCH2£h3).
Mp: 169 - 170°C.
AP/P/ 95/00723 BAD ORIGINAL d
AP Ο Ο Ο 3 β 8
-290Sxample 362
Ν- (2- (2-Ethoxv-6-fluoro)phenethvl) -Ν' - (2PhiaQaQlY.1 J PhiQurea
1) 3-Fluorophenol (20.0 g, 178.4 mmol), ethyl iodide (83.5 g, 535.2 mmol) and K2CO3 (49.3 g, 356.8 mmol) in 250 ml of acetone were stirred at 50°C overnight. The mixture was filtered and evaporated to give i-ethoxy-3-fluorobenzene.
Yield 19.84 g (79%) .
!h-NMR (250 MHz, CDCI3): 67.20 (q, IH, phenyl), 6.69 6.57 (m, 3H, phenyl). 4.00 (q, 2H, CH2CH3), 1.40 (t,
3H, CH2CH3).
2) 1.6 M Butyl lithium in hexane (24 ml,
38.4 mmol) was added slowly (0.5 h) to a solution of l-ethoxy-3-fluorobenzene (5.0 g, 35.7 mmol) in 100 ml of dry THF at -65°C under nitrogen. The solution was stirred at -65°C for 25 min. DMF (5.22 g, 71.4 mmol) was added dropwise to the solution. The mixture was allowed to warm to room temperature. 300 ml of ice was poured to this mixture and it was extracted with diethyl ether. Diethyl ether was washed with brine, dried over Na2SO4 and evaporated. The product was purified by silica gel column chromatography (EtGAc/petroleum ether 10:100) to give 2-ethoxy-6fluorobenzaldehyde.
Yield: 3.69 g (61 %).
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-291l-H-NMR (250 MHz, CDCI3): δ7.52 - 7.40, 6.80 - 6.64 (m, 3Η, phenyl), 4.18(q, 2H, ΟΗ2ΟΗ3), 1.50 (t, 3H,
CH2CH3).
13C-NMR (250MHz, CDCI3): δΐ88, 165, 161, 136, 109,
108, 65, 14.
3) Following the procedure of Example 151, this aldehyde was transformed to 2-(2-ethoxy-efluorophenyl ) ethylamine, which was condensed with the product of Example 103, using the procedure of Example 105 to give the titled product.
3H-NMR (250 MHz, DMSO): δ7.32 - 6.72 (m, 5H, phenyl, thiazole), 4.00 (q, 2H, CH2CH3), 3.78 (q, 2H, CH2-NH), 2.92 (t, phenyl-CH2), 1.33 (t, 3H, ΟΗ2ΟΗ3).
Example ,.261
N-(2 - (3 -1sopropoxv)phenethvl)-N'- (2-thiazolyl) thiourea
3-Isopropoxybenzaldehyde was prepared from
3-hydroxybenzaldehyde and isopropyl iodide analogous to the procedure described in Example 361. By using the procedure of Example 151 this aldehyde was transformed to 2- (3-isopropoxyphenyl)ethylamine, which was reacted with the product of Example 103, following the procedure of Example 105 to give the titled product.
^-H-NMR (250 MHz, DMSO): 07.44 - 6.84 (m, 6H, phenyl, thiazole), 4.69 - 4.64 (m, IH, isopropoxy-CH), 3.87 iq, 2H, CH2NH), 2.96 (t, 2H, phenyl-CH2), 1.36 - 1.32 (m, 6H, 2CH3).
£ 2 Z 0 0 / g 6 /d/dV
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AP Ο Ο Ο 3 8 8
-292Example 36.1
Nr (2,-,15 7ΒΐΌΐιΐΩ72ν£ΐ±οχγ)Εΐΐ£η£ί1ΐγΙ-Ν' cL2thi a zoly 11 thiourea
1) 5-Bromo-2-hydroxybenzylalcohol (5.0 g,
24.6 mmol), ethyl iodide (11.5 g, 73.8 mmol) and K2COj i3.4 g, 24.6 mmol) in 50 ml of acetone was stirred at *50°C overnight. The mixture was filtered and evaporated. The product was purified by silica gel column chromatography (EtOAc/petroleum ether 30:100) to give 5-bromo-2-ethoxybenzyl alcohol.
Yield: 5.24 g (92 %).
1H-NMR (250 MHz, CDCI3): 67.42 - 7.31 (m, 2H, phenyl), 6.73 (d, IH, phenyl), 4.67 (d, 2H, £H2-OH), 4.07 (q,
2H, Ch2CH3) . 1.60 (s, IH, OH), 1.43 (t, 3H, CH2££l3) ·
2) 5-Bromo-2-ethoxybenzyl alcohol (2.78 g, 12.0 mmol) and pyridinium dichromate (4.51 g, 12.0 mmol; in 120 ml of CH2C12 was stirred at RT for 6 h. The mixture was filtered, washed with H2O, 0.5 N HCl and brine and dried over Na2SO4· The product was purified by silica gel column chromatography (EtOAc/petroleum ether 10:100) to give 5-bromo-2ethoxybenzaldehyde.
Yield: 2.33 g (85 %).
-H-NMR (250 MHz, CDCI3): δ 10.4 (s, IH, CHO), 7.91 (d,
IH, phenyl), 7.60 (dd, IH, phenyl), 6.88 (d, IH, phenyl), 4.14 (q, 2H, CH2CH3), 1.51 (t, 3H, CH2CH3).
AP/P/ 95/00723
3) Following the procedure of Example 151,
AP Ο Ο Ο 3 8 8
-293ethoxyphenyl)ethylamine, which was condensed with the product of Example 103, using the procedure of Example 105, to give the titled product.
1H-NMR (250 MHz, DMSO): 8 7.10 - 6.62 (m, 5H, phenyl, thiazole), 3.73 (q, 2H, CH2CH3) , 3.52 (q, 2H, CH2NH) ,
2.62 (t, 2H, phenyl-CH2), 1.07 (t, 3H, ΟΗ2ΟΗ3).
Example 365
N- (2 - (2,5-Dimethoxy)phenethyl) -Ν' - (2-pvridvl) thiourea 10 2,5-Dimethoxy phenethylamine (0.36 g, 2.0 mmcl) in 7 ml of DMF was added to a solution of 1,1chioearbonyldiimidazole (0.36 g, 2.0 mmol) in 7 ml of DMF at 0°C. After 5 minutes 2-aminopyridine (0.19 g,
2.0 mmol) in 7 ml of DMF was added at 0°C.
This mixture was refluxed at 150°C for 4 hours. After cooling to room temperature it was poured into ice-water and extracted with diethyl ether, dried over Na2SO4 and the solvent was evaporated. The product was purified by silica gel column chromatography (EtOAc/petroleum ether 15:100). Yield: 0.24 g (39 %).
!h-NMR (250 MHz, CDCI3): δ9.41 (broad S, IH, NH) , 8.04 (d, IH, pyridine), 7.61 (t, IH, pyridine), 6.94 - 6.67 (m, 5H, phenyl, pyridine), 4.03 (q, 2H, CH2NH), 3.78 is, 3H, CH3O), 3.73 (s, 3H, CH3O), 3.00 (t, 2H,
AP/P/ 95/00723
AP Ο Ο Ο 3 8 8
-294Εχample .3 66
Μ-, 12.t.L2.tfithoxy) phenethy 112.- (5bromo) pyridyl] thiourea
In a manner analogous to Example 151, 25 ethoxy phenethylamine was obtained from 2ethoxybenzaldehyde.
2-Ethoxy phenethylamine (1.1 g, 6.7 mmol) in 20 ml of acetonitrile was added slowly to a mixture of 1,I-thiocarbonyldiimidazole (1.32 g, 7.4 mmol) in 20 ml of acetonitrile at 0°C. The mixture was warmed to RT and evaporated. 2-Amino-5-bromo-pyridine (1.63 g,
9.4 mmoi) and this crude reaction mixture in 30 ml of DMF were refluxed for 6 h at 140°C. After cooling to room temperature the reaction mixture was poured into ice-water and extracted with diethyl ether, dried over
Na2SC»4 and the solvent was evaporated. The product was purified by silica gel column chromatography (EtOAc/petroleum ether 15/100).
l-H-NMR (250 MHz, CDCI3 )5 8.73 (broad S, IH, NH) , 8.00 (d, IH,. pyridine), 7.68 (dd, IH, pyridine), 7.26 7.16 (m, 2H, phenyl), 6.96 - 6.82 (m, 2H, phenyl),
6.68 (d, IH, pyridine), 4.03 (q, 2H, CH2CH3), 4.03 (q, 2H, CH2NH), 3.02, (t, 2H, phenyl-CH2), 1.42 (t, 3H, CH2CH3).
13C-NMR (250MHz, CDCl3)5l79, 157, 152, 146, 141,
131, 128, 127, 120, 113, 112, 111, 63, 46, 30, 15.
AP/P/ 95/00723
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-295Exaniplfi·, 3 67
Ν-(2-(2-Ethoxy-6-fluoro)phenethyl)-Ν’ -(2pvridvl) thiourea
The starting material 2-(2-ethoxy-65 fluorophenyl)ethylamine was prepared as described in
Example 362. Following the condensation procedure described in Example 366, and using 2-aminopyridine instead of 2-amino-5-bromopyridine, the titled product resulted.
1C iH-NMR (250 MHz, CDC13) 58.00 (d, IH, pyridine), 7.58 (t, IH,. pyridine), 7.14 (q, IH, pyridine), 6.91 - 6.59 (m, 4H, phenyl, pyridine), 3.95 (q, 2H, CH2CH3), 3.95 (q, 2H, CH2-NH), 3.09 (t, 2H, phenyl-CH2), 1.39 (t,
3H, CH2CH3).
13C-NMR (250 MHz, CDCl3)8l79, 164, 153, 145, 138,
128, 128, 117, 112, 108, 107, 107, 64, 45, 22, 15.
Example.J.68
N-2-(2-Methoxv)phenethyl)-N1-(2thiazQlyllmethvlthiQether
Methyl iodide (0.425 g, 3.0 mmol) was added to a solution of N-(2-(2-methoxy)phenethyl)-Ν'-(2thiazoiyl) thiourea, (Example 94), (0.3 g 1.0 mmol) in
15 mi of DMF. The mixture was stirred at RT for 8 h.
Methyl iodide was evaporated and the mixture was poured to ice, extracted with methylene chloride, dried over Na^SO^ and evaporated. The product was purified by silica gel column chromatography (EtOAc/petroleum ether 10:100).
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AP Ο Ο Ο 3 8 8
-296!h-NMR (250 MHz, CDCI3): δ7.25 (d, IH, thiazole), 7.24
- 7.16 (m, 2H, phenyl), 6.92 - 6.81 (m, 2H, phenyl),
6.70 (d, IH, thiazole), 3.79 (s, 3H, CH3O), 3.57 (q,
2H, CH2NH), 2.95 (t, 2H, phenyl-CH2), 2,46, (s, 3H,
SCH3) .
13C-NMR (250 MHz, CDCI3): δΐ73, 162, 157, 137, 130,
127, 126, 120, 111, 110, 55, 43, 30, 13.
Example 369
N- (2-(2-Ethoxv-6-fluoro)phenethyl)-Ν'-(2-(5methvl) pyridyl! thiourea
The starting material 2-(2-ethoxy-6fluorophenyl)ethylamine was prepared as described in Example 362. Following the condensation procedure described in Example 366 and using 2-amino-5methylpyridine instead of 2-amino-5-bromopyridine, the titled product resulted.
iH-NMR (250 MHz, CDCI3): 6 8.65 (broad s, IH, NH) , 7.83 (s, IH, pyridine), 7.41 (d, IH, pyridine), 7.22 - 7.05 (q, IH, phenyl), 6.73 - 6.58 (m, 3H, phenyl, pyridine), 3.98 (q, 2H, £H2CH3) , 3.98 (q, 2H, .
3.07 (t, 2H, phenyl-£H2), 2.25 (s, 3H, CH3), 1.40 (t, 3H, CH2Cfi3).
13C-NMR (250 MHz, CDCI3): 6179, 168, 152, 145, 139,
127, 127, 126, 111, 108, 108, 107, 63, 44, 22, 17, 14.
Example 370
Nr Phenethyl-_N(2- (Srchloro) pvridvl) thiourea
The product from example 374 (0.3 g, 1.76
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-297of acetonitrile was stirred at RT for 0.5 h. The mixture was filtered. The precipitate was dried and recrystallized from acetonitrile.
Mp: 152 - 153CC.
^H-NMR (250 MHz, DMSO): δ8.20 (d, IH, pyridine), 7.98 (dd, IH, pyridine), 7.45 - 7.40 (m, 5H, phenyl), 7.27 (d, IH, pyridine), 3.94 (q, 2H, CH2NH), 3.04 (t, 2H, phenyl-CH2).
13C-NMR (250 MHz, DMSO): δΐ79, 152, 143, 139, 139,
129, 128, 126, 124, 114, 46, 34.
Example 371
N- (cis- (D,L) -2-Phenvlcvclopropvl) -Ν’ - (2pyridvll,thiourea τ cis-(D, L)-2-Phenylcyclopropylamine (Example
348) and 2-aminopyridine were reacted according to the procedures of Examples 93 and 94, using 2aminopyridine instead of 2-aminothiazole, to give the titled product.
iH-NMR: 1.19 - 1.27 (m, IH) , 1.45 - 1.55 (m, IH), 2.50 (q, IH), 3.67 - 3.78 (m, IH) , 6.73 - 6.78 (m, 2H) ,
7.27 - 7.34 (m, 5H), 7.41 - 7.53 (m, 2H) , 1.08 (broad s, IH).
13C-NMF.: 12.4, 21.9, 34.6, 111.8, 117.3, 126.5, 128.2,
129.1, 136.5, 138.2, 145.1, 153.0, 180.3.
AD'°' 9 5 / η n 7 ? 3
AP Ο Ο Ο 3 8 8
-298Example 372
Μ.-.1 5.-.Chip ra.·: 2 z pyridyl) -Ν' - (cis- (D.L) -2.-.
phenY-lgyclQpropyl 1 thiourea cis- (D, L)-2-Phenyl cyclopropylamine (Example
348/ and an activated derivative of 2-amino-5chloropyridine, i.e. 1-(2-amino-5-chloropyridine)-1·imidazole-thiocarbonyl, were condensed using the procedures of Example 105 to give the titled product. 1h-NMR (CDCI3): 1.19 - 1.26 (m, IH), 1.46 - 1.55 (m,
1H), 2.51 (q, 1H> , 3.64 - 3.74 (m, IH), 6.74 (dd, IH),
7.30 - 7.40 (m, 6H), 7.47 (dd, IH), 9.2 (broad s, IH).
10.9 (broad s, IH).
i^c-NMR (CDCI3): 12.4, 22.0, 34.7, 112.7, 124.7,
126.8, 128.4, 129.2, 136.5, 138.3, 143.9, 151.1,
180.2.
Mp: 194 - 195.5°C.
Example 373
N- (5-Bromo-2-pyridvl) --N? - (cis- (D.L) -220 phenylcvclopropvl) thiourea cis- (D,L)-2-Phenylcyclopropylamine (Example
348) and 2-amino-5-bromopyridine were reacted according to the procedures of Examples 93 and 94, using 2-amino-5-bromopyridine instead of 225 aminothiazole, to give the titled product.
iH-NMR (CDCI3): 1.19-1.26 (m, IH) , 1.47 - 1.55 (m,
IH), 2.52 (q, IH), 3.66 - 3.75 (m, IH), 6.66 (dd, IH), 7.27 - 7.41 (m, 5H>, 7.47 (d, IH), 7.60 (dd, IH), 8.98 (broad s, IH), 10.88 (broad s, IH).
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-29913C-MMR (CDCI3): 12.4, 22.0, 34.7, 112.3, 113.1,
126.8, 128.4, 129.2, 136.5, 140.9, 146.2, 151.3,
180.2.
Mp: 20.4 - 205° C
Anal, calcd. for C^H^er^S: C, 51.7; H, 4.05; N, 12.07. Found C, 51.5; H, 4.0; N, 12.0.
Example 374
5-Chloropvrid-2-vlisothiocvanate
2-Amino-5-chloropyridine (10.28 g) was added in portions, with stirring, over a period of 25 minutes to a solution of thiocarbonyl diimidazole (14.26 g) in acetonitrile (100 ml) at ambient temperature. The stirring was continued and the solution/suspension was left at ambient temperature for a few hours. The precipitate was filtered and washed with acetonitrile (3 x 25 ml). The solid residue was dissolved in hot acetone and filtered.
The acetone solution was evaporated in vacuo, the residue was dissolved in hot ethyl acetate and filtered through a pad of silica (diam. 7 c m x 3 cm). The silica was washed with another portion of hot ethyl acetate. The combined solutions were evaporated in vacuo to yield a crude product (5 g) of the titled product.
!h-NMR (DMSO): 7.54 (d, J = 8.7 Hz, IH) , 8.17 (dd, J = 2.7, 8.7 Hz, IH), 8.63 (d, J = 2.7 Hz, IH).
13C-NMR (DMSO): 121.4, 130.1, 139.4, 140.7, 143.9, 143.6.
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APO00388
-300Examale, 375
N-Cis- ίΡ,Ιΰ thiazolyl.}thiourea
The starting material, 3-methoxystyrene, was 5 prepared in following manner:
To a mixture of 26.2 g (73.4 mmol) of methyl triphenylphosphonium bromide in 200 ml of THF cooled to 0°C, was added 42 ml (2M in THF, 82 mmol) of a lithium diisopropyl amide solution over 30 min. The mixture was stirred for an additional 2 hours then 10 g (73.4 mmol) 3-methoxybenzaldehyde was added dropwise over 25 min. The reaction mixture was stirred for one hour at room temperature and then heated under reflux for 14 hours. After cooling the solvent was evaporated in vacuo, the residue was diluted with 200 ml diethyl ether and the precipitate was removed by filtration. The ether solution was washed with water, dried with Na2SO4 and evaporated in vacuo. The product was purified by silica gel column chromatography (diethyl ether/cyclohexane) .
Yield: 2.83 g (29 %) .
1h-NMR (CDCl3)d: 7.24 ft, J = 8.1 Hz, IH, Ph), 7.216.98 (m, IH, Ph), 6.95 (t, J = 2.3 Hz, IH, Ph), 6.81 (ddd, J. = 8.1 Hz, 2.3Hz, 0.9 Hz, IH, Ph), 6.69 (dd, J = 17.6 Hz, 10.8 Hz, IH, CH), 5.74 (dd, J = 17.6 Hz,
0.9 Hz, IH, CH2), 5.25 (dd, J = 10.8 Hz, 0.9 Hz, IH, CH2), 3.81 (s, 3H, CH3).
13C-NMR (CDCl3)d: 159.81 (C-3), 139.04 (C-l), 136.79 (C-a), 129.51 (C-5). 118.92 (C-6), 114.15 (C-4),
113.46 (C-2), 111.53 (C-b), 55.22 (O-£H3).
AP/P/ 9 5 / 0 0 7 2 3 bad original g
AP Ο Ο Ο 3 β 8
-301The titled compound was prepared in a manner analogous to the procedures described in Examples 348 and 349, using 3-methoxystyrene instead of styrene. 1H-NMR (CDCl3)d: 7.26-7.19 (t and d, 2H, o and thiazole), 6.90-6.69 (m, 4H, o, m, p, thiazole), 3.76 (s, 3H, OMe), 3.65 (broad s, IH, NH-CH-), 2.50 (q, IH, Ph-Ch-), 1.22 (m, 2H, Cyclopropyl).
13C-NMR (CDCl3)d: 178.6 (C=S), 161.3 (thiazole), 159.8 (£-OMe), 137.8 (Ph), 137.7 (thiazole), 129.5 (Ph),
121.6 (Ph), 114.5 (Ph), 112.8 (Ph), 111.0 (thiazole),
55.2 (O-£H3), 44.0 (£H-NH), 22.0 (£H-Ph), 12.1 (£H2).
Example 376
N-cis-(D,L) - (2- (2-Fluorophenvl)cvclopropvl) -Ν'- (215 .thj-azayl -Lhiour.ea
In a manner analogous to the procedures described in Examples 348 and 349 and using 2fluorostyrene instead of styrene, the titled product was prepared.
iH-NMR (CDCl3)d: 7.32-7.05 (m, 4H), 6.91-6.64 (m, 2H),
3.68 (broad s, IH, Cfl-NH), 2.57 (q, IH, CH-Ph), 1.701.40 (m, 3H) , 1.31-1.18 (m, IH).
13C-NMR (CDCl3)d: 178.8 (C=S), 162.5 and 160.5 (£-F,
Ph), 161.2 (thiazole), 137.4 (thiazole), 129.9 (Ph),
128.5 and 128.4 (m to F,Ph), 124.0 (p to F, Ph) 115.4 and 115.1 ( o to F, Ph), 111.8 (thiazole), 33.8 (£HNH), 16.4 (£H-Ph), 12.2 (£H2).
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V.
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-302Εχample 377
Ν- (2-f3 - (6-ChlorQ-2-methQXY)Pvridvllethvl) -Ν/-(2-(5bromo)pvridvl)thiourea
The starting material, 3-(2-aminoethyl,-6-chloro5 2-methoxypyridine, was prepared in following manner:
To a solution of 1.0 g (7.0 ramol) of 2chloro-6-methoxypyridine in 20 ml of dry THF cooled to -78°C was added 10.9 ml (1.6 M in hexanes, 17.4 mmol) η-BuLi under an atmosphere of nitrogen. The temperature of the mixture was allowed to raise to
-40°C before an addition of 4 ml ethylene oxide in 6 ml ether. The mixture was warmed to room temperature, 50 ml water was added and the aqueous layer was separated and extracted with 2 x 100 ml EtOAc. The organic extracts were combined, washed once with water, dried with Na2SC>4, and concentrated in vacuo.
The crude material was purified by dry column flash chromatography (hexane/EtOAc ) to afford 0.22 g of 3(2-hydroxyethyl)-6-chloro-2-methoxypyridine as a yellowish oil.
To a solution of 0.20 g (0.8 mmol) ot 3-(2hydroxyethyl)-6-chloro-2-methoxypyridine in 10 ml of dry CH2CI2 cooled to -50°C was added 0.18 ml (0.8 mmol) trifluoromethanesulfonic anhydride under an atmosphere of nitrogen. The mixture was stirred for min at this temperature and an additional 10 min at -78°C before a rapid addition of 30 ml of cold (-78°C) NH3 (1). The mixture was stirred for 15 min at room temperature, and then concentrated in vacuo to afford
1.0 g of crude 3-(2-aminoethyl)-6-chloro-2-_
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-303methoxypyridine as a trifluoromethanesulfonic acid salt.
^H-NMR (CD3OD)d: 7.66 (d, lH, Py), 7.03 (d, IH, Py), 4.04 is. 3H, CH3-O), 3.24 (t, 2H, CH2-N), 3.03 (t, 2H,
CH2-Py).
The crude 3-72-amineethyl)-6-chloro-2methoxypyridine was condensed with N-(2-(5bromo) pyridyl-N'- (1-imidazolyl) thiourea in a manner analogous to Example 103, to give the titled product.
10 1H-NMR (CD3OD)d: 11.25 (broad s, IH, N-H) , 10 .82
(broad s, IH, N-H), 8.31 is. IH, Br-Py), 8.08 (d, IH,
Br-Py), 7.89 (d, IH, Cl-Py), 7.21 (m, 2H, Cl- and Br-
Py), 3.96 (m, 5H, CH2-N, and CH3-O), 3.03 (t, 2H, ch2-
Py) .
13C-NMR (CD3OD)d: 179.45 (C=S), 161.43 (Cl-C in Py) ,
152.41 (Br-C in Py), 145.92 (Cl-Py), 145.14 (MeO-CPy), 141.89 (Br-Py), 141.51 (Br-Py), 120.32 (Cl-Py), 116.48 (Cl-Py), 114.60 (Br-Py), 111.95 (Br-Py), 55.10 (CH3-O), 43.76 (CH2-NH!, 27.89 (CH2-Ph).
Example,378
N- (2 713-..( 2 TFluoro) pvridvl I ethvl) -Ν' -(2-(5frEpmaJ pyridyl)thiourea The starting material, 3-(2-aminoethyl)-225 fluoropyridine, was prepared in following manner:
A solution of 2.0 g (20.6 mmol) of 2fluoropyridine in 25 mi of dry THF was cooled to -78°C was added 25 ml (1.6 M in hexanes, 41.6 mmol) n-BuLi under an atmosphere of nitrogen. The mixture was stirred at this temperature for 2 hours before an addition of 4 ml ethylene oxide in 7 ml ether. The
AP./P/ 95/00723 bad original
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-304mixture was wanned to room temperature, 150 ml ether and 25 ml acetone was added. The precipitate was removed by filtration, and the filtrate was concentrated to 1/3 of volume in vacuo. The remainder was washed once with brine, dried with Na2SO4, and concentrated in vacuo. “The crude material was purified by dry column flash chromatography (hexane/EtOAc) to afford 0.42 g of 3-(2-hydroxyethyl)2-fluoropyridine as a brown oil.
To a solution of 0.20 g (1.42 mmol) of 3-(2hydroxyethyl)-2-fluoropyridine in 8 ml of dry CH2C12 cooled to -40°C was added 0.18 ml (0.8 mmol) trifluoromethanesulfonic anhydride under an atmosphere of nitrogen. After stirring for 30 min at -40°C, 30 ml of cold (-78°C) NH3 (1) was added. The mixture was stirred, for 30 min at -40°C, and then concentrated in vacuo to afford 1.03 g of crude salt which was washed twice with 20 ml diethyl ether to yield 0.82 g of 3(2-aminoethyl)-2-fluoropyridine as a trifluoromethanesulfonic acid salt.
iH-NMR (CD3OD,d: 8.23 (d, 1H, Py), 7.98 (t, 1H, Py) ,
7.40 (m, IK, Py), 3.30 (t, 2H, CH2-N). 3.12 (t, 2H, CH2-Py).
The crude 3-(2-aminoethyl)-2-fluoropyridine was condensed with N-(2-(5-bromo)pyridyl-Ν'-(1imidazoiyl) thiourea in a manner analogous to example 103, to give the titled product.
2H-NMF. (CD3OD)d: 8.31 (d, 1H, Br-Py), 8.23 (m, 1H, FPy), 8.06 (m, 2H, Br-and F-Py), 7.45 (m, 1H, F-Py),
AP/P/ 95/00723 bad ORIGINAL £
ΑΡ 0 0 0 3 8 8
-3057.23 (d, ΙΗ, Br-Py), 4.00 (q, 2Η, C^-Ni , 3.14 (m, 2Η, cH2-py>· 13C-NMR (CD3OD)d; 179.59 (C=S), 163.53 and 159.78 (F-£ in Py), 152.39 (Br-Py), 145.87 (F-Py),145.63 and
142.38 (F-Py), 142.28 (Br-Py),141.54 (Br-Py), 122.31 and 122.26 (F-Py), 120.^4 and 120.45 (F-Py), 114.59 (Br-Py), 111.97 (Br-Py), 44.29 (£H2-NH) , 27.32 (£H2Ph) .
Example 379
N- (2- (2., 6-difluoro) phenethvl) -Nz- (2-benzothiazolyl) thip.ur.ea
In a manner analogous to Example 105, 2,6difluorophenethylamine was condensed with 1-(215 aminobenzothiazole)-1'-imidazole thiocarbonyi which was made in similar way as described in Example 103.
The titled compound crystallized from methylene chloride.
J-H-NMR (CDC13 + CD3OD) d: 7.64 (m, 2H, benzo), 7.38 (m, 3H, DFPh, benzo), 7.24 (t, 2H, DFPh), 4.04 (t, 2H,
CH2), 3.15 ( t, 2H, CH2).
Example 380
N-i2-.L2-x.6cdifluoro)phenethyl) -Ν' - (2-(4.525 dimethyl)thiazolyl) thiourea
In a manner analogous to Example 105, 2,6difluorophenethylamine was condensed with 1- (2-amino4,5-dimethylthiazole) - 1imidazole thiocarbonyi which was made in a similar way as described in Example 103.
AP/P/ 9 5 / 0 0 7 2 3
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-306The titled compound crystallized from methylene chloride.
1-H-NMR (CDCI3) d: 7.21 (m, IH, DFPh), 7.15 (t, 2H, DFPh). 4.00 iq, 2H, CH2), 3.09 (t, 2H. CH2 ) , 2.22 (d,
J=0.5Hz, 3H, Me), 2.08 id, J=0.6Hz, 3H, Me).
Example. .2.8.1
N- (2 - (2-fluoro)Phenethyl) -N1 - (2- L6.r.
flyproke.aapthiaaalYll.t,hipurea
In a manner analogous to Example 105, 2£luorophenethylamine was condensed with l-(2-amino-6fluorobenzothiazole)-1 *-imidazole thiocarbonyl which was made in a similar way as described in Example 103. The titled compound crystallized from methylene chloride.
1H-NMR(CDCl3 + CD3OD) d: 7.53-7.06 (m, 7H, benzo,
FPh), 4.04 (t, 2H, CH2), 3.10 it, 2H, CH2).
Example 282
N-(2- (2 /, 6-dif luorolph^nethyU-tN '.-L2zlL·.
IluQxahenzQthiazQlyl)thiourea
In a manner analogous to Example 105, 2,6difluorophenethylamine was condensed with l-(2-amino6--f luorobenzothiazole)-1'-imidazole thiocarbcnyl which was made in a similar way as described in Example 103. The titled compound crystallized from methylene chloride .
/•H-NMR :CDCl3 + CD3CD) d: 7.52 (m, IH, benzo), 7.40 (m, IH, benzo), 7.14 (m, 2H, DFPh, benzo), 6.88 (m,
2K, D^Phi, 4.02 (t, 2H, CH2), 3.14 (t, 2H, CH2).
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N-(2-(2-fluoro)phenethvl)-Ν' -(2-307Example 383 benzothiazolvl) thiourea
In a manner analogous to Example 105, 2fluorophenethylamine was condensed with 1-(2aminobenzothiazole)-1'-imidazole thiocarbonyl which was made in a similar way as described in Example 103. The titled compound crystallized from methylene chloride.
1h-NMR (CDCI? + CD3OD) d: 7.63 (q, 2H, benzo), 7.32 (m, 4H, benzo, FPh), 7.10 (q, 2H, FPh), 4.06 (t, 2H, CH2), 3.11 it, 2H, CH2).
Example 384
H- (2 - (2 -fluoro)phenethvl) -N' -(2-(4methvlthiazolyl) thiourea
In a manner analogous to Example 105, 2fluorophenethylamine was condensed with 1-(2-amino-4methylthiazole)-1'-imidazole thiocarbonyl which was made in a similar way as described in Example 103.
The tided compound crystallized from methylene chloride .
AP/P/ 9 5 / 0 0 7 2 3
1h-NMR !CDC13 + CD3OD) d: 7.23 (m, 2H, FPh), 7.06 (m, 2H, FPh), 6.34 (d, J=lHz, IH, thiazole), 3.99 ( t, 2H,
Example,385
N- i2- (2,6.r.difluoro)phenethvl) -Ν' - (2-(4methvlthiazolvl)thiourea
In a manner analogous to Example 105, 2,6difluorophenethylamine was condensed with l-(2-amino-_ __
AP Ο Ο Ο 3 8 β
-3034-raethyIthiazole)-1'-imidazole thiocarbonyl which was made in a similar way as described in Example 103.
The titled compound crystallized from methylene chloride.
-H-NMR (CDCI3 + CD3OD) d: 7.19 (m, IH, DFPh), 6.87 (t,
2H, DFPh), 6.35 (s, IH, thiazole), 3.98 (t, 2H, CH2), 3.09 it, 2H, CH2), 2.22 s, 3H, Me).
Example. 386
N- (2,2-dimethyl-2- (2-chlorQ-.6.-fluoro)ohenethvl) -Nz-(2thiazolvl)thiourea
A solution of 2-chloro-6-fluorophenyl acetonitrile (1.69 g, 10 mmole) in dry THF (70 ml) was cooled to -60°C, and lithium diisopropylamide (5.25 ml, 10.5 mmole) was added. After 30 min, methyl iodide (0.68 ml, 11 ml ) was added into the reaction mixture, and the reaction was slowly warmed to 0°C, and kept at 0° C for 1 hr. Then it was cooled to -60°C again, and more lithium diisopropylamide (6 ml, 12 mmole) was added. After 30 min, methyl iodide (1.87 ml, 3 0 mmole) was added. The reaction mixture was allowed to warm to room temperature and kept there for 2 hr after which it was poured into a sodium hydrogen carbonate solution, and extracted with chloroform.
The organic phase was washed with water, dried, and the solvent was evaporated in vacuo. The product 2,2dimethvi-2 .2-chloco-6-fluorophenyl) acetonitrile (1.07
g) was isolated by silica gel column chromatography. iH-NMR (CDCI3) d: 7.25 ( ra, 2H, Ph), 7.03 ( m, IH,
Ph), 1.S8 is, 3H, Me ), 1.96 (s, 3H, Me).
AP/P/ 95/00723
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AP Ο Ο Ο 3 8 8
-309The 2,2-dimethyi-2-(2-chloro-6fiuorcphenyl)ethylamine was obtained by reduction of
2,2-dimethv1-2 ί2-chloro-6-fluorophenyl) acetonitrile with cobalt chloride and sodium borohydride according ό to the method described by L.S. Heizman in J. Am.
Chem. Soc , 104, p.6801, (1980). It was then condensed with 1-(2-aminothiazole)-I'-imidazole thiocarbonyl in the analogous manner to Example 105. The titled compound was isolated by silica gel column chromatography.
Ικ-NMR (CDCI3) d: 7.35-7.09 (m, 3H, Ph), 6.95 ( d, IH, thiazole), 6.73 ( d, IH, thiazole), 4.09 (d, 2H, CH2), 1.50 ( s, 6K, Me ).
Example 3§7
N- (2-(5-bromo-2-methoxy)phenethyl)-Nz-(2-(4methvlthiazolyl)thiourea In a manner analogous to Example 105, 5bromo-2-methoxyphenethylamine was condensed with 1-(220 amino-4-methylthiazole)-1'-imidazole thiocarbonyl which was made in a similar way as described in Example 103. The titled compound crystallized from methylene chloride .
-H-NMR (CDCI3 + CD3OD) d: 7.31 (d, IH, Ph), 7.29 (s,
IH, Ph), 6.72 (d, IH, Ph), 6.34 (s, IH, thiazole),
3.95 (t. 2H, CH2), 3.79 (s, 3H, MeO), 2.96 (t, 2H, CH2). 2.23 (s, 3H, Me).
AP/P/ 9 5 / 0 0 7 2 3 Bad original
AP Ο Ο Ο 5 8 5
-310kJ’
Εχample 288
Ν-'2-(5-bromo-2-methoxv)phenethvl)-Νζ-(2- (4cyanothiazalyli thict-ursa In a manner analogous to Example 105, 5bromo-2-methoxyphenethyl-amine was condensed with 1(2-aminc-4-cyanothiazole)-1'-imidazole thiocarbonyl which was made in a similar way as described in Example 103. The titled compound was purified by silica gel column chromatography.
i-H-NMR (CDCI3 + CD3OD) d: 7.51 (thiazole), 7.32 (d,
IH, Ph), 7.27 (s, IH, Ph), 6.76 (d, IH, Ph), 3.90 (t, 2H, CH2), 3.83 is, 3H, MeO), 2.97 (t, 2H, CH2).
Example 389
N- (2 - (2.6-difluoro)Phenethyl)-N‘-(2-(4cvano-thiazolvl) thiourea
In a manner analogous to Example 105, 2,6difluorophenethylamine was condensed with l-(2-amino4-cyanothiazole)-1'-imidazole thiocarbonyl which was made in a similar way as described in Example 103.
The titled compound crystallized from methylene chloride .
;cdc13 + CDiOD) d: 7.51 (s, IH, thiazole), 7.22 (m, IH, DFPh), 6.90 't, 2H, DFPh), 3.93 (t, 2H, CH2), 3.08 (s, 2H, CK2).
AP/P' Q5 / η 0 7 2 3
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AP Ο Ο Ο 3 8 8
-311Example 39Q
Ν- (2-.(2^6-_difluoro)phenethyl)-Ν' - (2imidazolvl)thiourea
In a manner analogous to Example 93, using 5 2,6-difluorophenethylamine and 2-aminoimidazole, the titled compound was obtained.
(DMSO + D2O) d: 7.28 (m, 1H, DFPh), 7.02 (t,
2H, DFPh), 6.78 (broad, IH, imidazole), 6.62 (broad, IK. imidazole), 3.79 (t, 2H, CH2), 2.97 (t, 2H, CH2 ) .
Example 381
N-d-amino-2-(5--imidazolvl) -ethvl) -Ν' - (2- (5-methvl) thiazolyl)thiourea 1-(2-(5-methyl)-aminothiazole-1'15 imidazolethiocarbonyl (prepared as described in
Example 103, using 2-amino-5-methylthiazole instead of 2-aminothiazole) (4.06 mmol, 910 mg) and histamine (4.05 mmoi, 450 mg) in dimethylformamide (10 ml) was heated to 50°C for 3 hrs. The mixture was .j concentrated and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was dried over MgSC>4 and concentrated to give the titled compound in 43 % yield (463 mg).
NMR '250 MHz, DMSO-dg) δ2.18 (s, 3 H) , 2.80 (m, 2
H', 6.57 (s, 1 H), 6.90 (s, 1 H), 7.60 (s, 1 H).
Example 392
- ,2-Amino-5-bicmopyridvl).-! ‘.- (imidazclvl) thiocarbonvl
A mixture of 2-amino-5-bromcpyridine, 97% (25.0 g, 140 mmol) and 1,1'-thiocarbonyldiimidazole.
AP/P/ 9 5 / 0 0 72 3 bad original
AP Ο Ο Ο 3 8 8
-31290% (27.72 g, 140 mmol) in 300 mol of acetonitrile was stirred at ambient temperature overnight and then filtered. The precipitate was dried in vacuo to give the titled compound as a crude product which was stored and used for further condensations with various phenethylamines.
Yieid: 37.5 g <95 %) .
Example 393
1-(5-chloropvrid-2-vl-thiocarbamovl)imidazole
In a 500 ml reaction-flask, N,Nthiocarbonyl-diimidazole <60.9 g, 337 mmol) was dissolved in acetonitrile (400 ml) at 50°C with stirring. The solution was then cooled to 20°C. 215 Amino-5-chloropyridine (43 g, 337 mmol) was then added.
The solution was stirred for 35 minutes and kept at ambient temperature over night. The solution was filtered and the crystalline mass consisted of a mixture of needles and pellets. The pellets were separated mechanically and purified by fluidization wich a hair-dryer to give che titled product.
^H-NMR DMSO-dg δ ppm 7.1-7.2 (2H, s, imid) 7.5-7.6 (IH, d, orto-coupling, pyr.) 7.9-8.0 (IH, s, imid.) 8.1-8.2 (IH, d,d, pyr.) 3.6-8.7 (IH, d, meta-coupling, pyr.)
AP/P/ 95/0072 3
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APO 00 3 8 3
-313Example, 3.9,4
N-2-(2,5-dimethoxvphenylethvl)-N1- (2-(6fluorobeazoLhi^zolyl)J thiourea
450 mg 2,5-dimethoxyphenethylamine (2.5 mmo1) and 740 mg 1-((2-(6fluoro)benzothiazolyl) thiocarbamoyl) imidazole (2.5 mmol) (Example 80) in 5 ml acetonitrile were refluxed for one half hour. The mixture was cooled, and crystals were filtered off. Recrystallization from a mixture of ethanol and dimethylformamide gave 640 mg of the pure product as very fine needles.
Mp: 196°C 1H-NMR: 3.00 2H (t), 3.77 3H (s), 3.84 3H (s), 3.91 2H (m), 6.91-7.03 3H (m), 7.38 IH (m), 7.70 IH (m) , 7.94
IH (mi, 9.9 IH broad singlet, 12.0 IH broad singlet
Analysis CigHigFN3O2S2: calculated C 55.22 H 4.63 N 10.73; found: C 55.3 H 4.70 N 10.75
Example 395
N-2a.(T2,5.-dimethQxvphenvle.thyl) -Ν' - (2-(4methvlthiazolvl)) thiourea
1000 mg (4.46 mmol) 1-(2-(4methyithiazolyl) thiocarbamoyl) imidazole (prepared analogously co 1-(2-thiazolyl)thiocarbamoyl)imidazole described in Example 103, and 800 mg 2,5dimethoxyphenethylamine (4.42 mmol) in 7 ml acetonitrile were refluxed for one half hour. The mixture was cooled to 0°C, crystals were filtered off, rinsed with acetonitrile and dried. Recrystallization bad ORIGINAL
AP Ο Ο Ο 3 8 8
-314from ethanol-dimethylformamide gave 1.42 g of the pure product.
Mp: 210°C
-‘-H-NMR (DMSO-dg): 2.27 3H (s), 2.96 2H (t) , 3.78 3H
5 is), 3.33 3H is), 3.34 2H (m), 6.73 IH (s) , 6.85-7.04
3H (m)
Analysis C15KJ9N3O2S2· calculated C 53. 39 H 5.67 N
12.45; found: C 53.1 H 5.65 N 12.35
ExaffiEl£_12£
N-2-(-2,5-dimethoxvphenethyl)-N‘-(2-(2benzQthiazQlY-1.11 thiourea
556 mg 1-(2-benzothiazolyl)thiocarbamoyl) imidazole (2 mmol) (Example 66) and 362 mg 2,515 dimethoxyphenethylamine (2 mmol) in 5 ml acetonitrile were refluxed for one half hour. Recrystallization from ethanol-dimethylformamide gave 565 ma pure product.
iH-NMR (DMSC-dg): 3.02 2H (t), 3.77 3H (s), 3.85 3H (s), 3.93 2H (m), 6.92-7.04 3H (m), 7.38 IH (m), 7.53
IH im), 7.70 IH (m), 8.01 IH (m)
Analysis Ci8Hi9N3O2S2: calculated C 57.88 H 5.13 N 11.25; found: C 57.95 H 5.15 N 11.25
5 Example 397 (2., 7-dlJ7hlprp>.Dhgnylethyl)-N, - (2-thiazolvl) thiourea
9.3 g 2,6-Dichlorophenylacetonitrile (50 mmol) in 50 ml diethylether was added dropwise to a mixture of 5 g lithium aluminum hydride in 200 ml
3.0 ether. The mixture was heated to reflux, and reaction was allowed to take place for 2 hours. The mixture
AP/P/ 9 5 / 0 0 7 2 3
BAD ORIGINAL &
APO 0 0 3 8 8
-315was cooled to room temperature, and 5 ml water was added dropwise, followed by 5 ml 25 % sodium hydroxide in water. 10 ml water was then added, and the mixture was filtered. 10 ml acetic acid was added rapidly to the stirred filtrate. The 2,6dichiorophenethylammonium acetate that precipitated was filtered off and dried.
500 mg 2,6-dichlorophenethylammonium acetate (2 mmol), 10 0.42 g 1-(2-aminothiazole)-1'-imidazole thiocarbonyl (Example 103) and 0.5 g diisopropylethylamine were mixed in 5 ml acetonitrile and refluxed for 30 minutes. The mixture was then kept at 0°C for 17 hours and the crystals were filtered off.
Recrystallization from acetonitrile gave 265 mg of the titled product.
!h-NMR (DMSO-dg): 3.3 2H (t), 3.9 2H (m), 7.2. IH (d),
7.35-7.6 4H (m).
td£uu/S6 /d/dV
Example,
M-2-(2,,6-dichlorophenvlethvl)-N1 - (2- (4methvlthiazolvl)) thiourea
500 mg 2,6-dichlorophenylethylammonium acetate (2 mmol) (Example 397), 0.48 g 1-(2-(425 methvlthiazolyl)thiocarbamoyl) imidazole (prepared analogously to 1 -(2-thiazolyl)thiocarbamoyl) imidazole described ir. Example 103) (2 mm.ol) and 0.5 g diisupropyiethylamine were mixed in 5 mi acetonitrile and refluxed for 30 minutes. The mixture was cooled and crystals were filtered off. Recrystallization from acetonitrile gave 598 mg of the titled product.
bad ORIGINAL
-316-H-NMF. (DMSO-dg): 2.2 3Η (s), 3.3 2Η (t) , 4.0 2H (m) , 6.7 ιη (s), i .4 IH (m), 7.5 2H (m), 9.8 IH broad singlet, 11.7 IH broad singlet
Analysis Ci3Hi3Cl2N3S2: calculated C 45.09 H 3.78 N 5 12.13; found: C 45.45 H 3.9 N 12.55
Ex amp.l£-19-3.
Η- ί -2- ¢2,6-.dichlgEQghenYl)gthYl)-w -.(2.-.
frenggthiazglY.lLEhigurea
5C0 mg 2,6-dichlorophenylethylammonium acetate (2 mmol) (Example 397), 0.55 g 1-(2benzotniazolyl)thiocarbamoyl) imidazole (2 mmol) (Example 66) and 0.5 g diisopropyl-ethylamine were mixed in 5 ml acetonitrile and refluxed for 30 minutes. The mixture was cooled and crystals were filtered off. Recrystallization from acetonitrile gave 497 mg of the titled product.
.. .7-7 , — I-, - — g , j . 2 ci (1 , 4.0 2-. (n;) , 7.J- 7.7 6 ri (m) , 8.0 IH id), 10.0 IH broad peak, 12.1 IH broad peak.
Analysis CigKi3Cl2N3S2: calculated C 50.26 H 3.43 N 10.99; found: C 50.3 H 3.45 N 11.1
Example 400
N- (.2.- (3 .6-dichlorophenvl) ethvl) -N· -(2-(6(fluorobenzothiazolvl)) thiourea
50C mg 2,6-dichlorophenylethylammonium acetate (2 mmol) (Example 397), 0.59 g 1-((2-(6fluoro)benzothiazolyl) thiocarbamoyl) imidazole (2 mmol) (Example 80 and 0.5 g diisopropylethylamine
AP/P/ 9 5 / 0 0 7 2 3
BAD ORIGINAL
AP Ο Ο Ο 3 8 β
-317were mixed in 5 mi acetonitrile and refluxed for 30 minutes. The mixture was cooled and crystals were filtered off. Recrystallization from acetonitrile gave 542 rrg cf the titled product.
iH-NMR (EMSO-dg): 3.4 2H (t!, 4.0 2H (m), 7.3-7.4 2H !m) . 7.5-/.7 2H (m) , 8.0 IH (m) , 9.8 IH broad peak, 12.0 IH broads peak.
Analysis O]_5H]_2Cl2F'N3S2 : calculated C 48.00 H 3.02 N 10.50; found: C 48.25 H 3.1 N 10.6
Example,4¢1
N-(2-(2.6-difluoro-3-methoxvphenvl)ethvl )-N’-(-2thiazolvl) thiourea
6.25 ml 1.6M n-butyl lithium in hexane was added dropwise to a solution of 10 mmol 2,4difluoroanisole in 30 ml diethyl ether. The mixture was kept at -65eC during the addition. 3 ml vaa the;: addad, and the mixture was slowly (lh) allowed to warm to room temperature. The mixture was poured into a separation funnel containing 50 ml ice-water. The ether layer was separated, washed with 50 ml water and dried (Na2SO4). The
AP/P/ 9 5 / 0 0 7 2 3 solvent was evaporated, and the residue was redissoived in 50 ml ethanol. 2 g Ammonium acetate and 3 ml nitromethane were added and the mixture was retluxec for 3 hours. The solvent was evaporated, and the residue was partitioned between 5C ml dichlciomethane and 50 ml water. The organic layer was dried, and the solvent was evaporated.
AP Ο Ο 0 3 88
-318crystals of l-nitro-2(2,€-difluoro-3mechoxypheny1)ethene.
!η-ΝΜΕ (CDCI3): 3.9 3H (s), 6.9-7.1 2H (m), 7.8 1H (di , 8.1 1H (d).
420 mg l-nitro-2-{2,6-difluoro-3methoxyphenyl)ethene was dissolved in 50 ml terrahydrofurane and added dropwise under stirring to a solution of 2 g lithium aluminum hydride in 50 ml tetrahvdrofurane. The mixture was refluxed for 3 hours. The product amine was worked-up by the dropwise addition of 2 ml water followed by 2 ml 25% scdium hydroxide in water followed by 4 ml water.
The mixture was then filtered. The filtrate was extracted with 2 x 20 ml 1 M HCl. The aqueous layer was made basic by the addition of 50 ml 45 % scdium hydroxide solution, and then extracted with 3 x 50 ml aichloro-methane. The 2-(2,6-difluoro-3,ηοΐ-/phpp.vl' Pth·'!-amine obtained by the evaporation of solvent was pure enough for use in the next step.
1.2 2H broad singlet, 2.6 2H (m) , 2.7 2H (m) ,
3.65 3H is), 6.4-6.6 2H (m)
172 mg 2-(2,6-difluoro-3methoxyphenyl)ethylamine (1.0 mmol) and 210 mg 1-(2ammothiazole)-1 ’-imidazole thiocarbonyl (1.0 mmol) in
5 m. acetonitrile were refluxed for one hour. The solucion was cooled, and crystallization was allowed for overnight. Solid material was filtered off, and recrysral1ized from acetonitrile to give 138 mg of the
AP/P/ 95/00723
AP Ο Ο Ο 3 8 8
-3191H-N14R (DMSO-dg): 3.1 2Η (t), 3.8-4.0 5H (m), 6.9-7.2 3H (m) , 7.4 IH (d) , 9.8 IH broad peak, 11.7 IH broad peak
Analysis C13H23F2N3OS2: calculated C 47.40% H 3.98% N 5 12.76%; found: C47.6% H 4.1% N 12.75%
Example 402
N- (2-.L-2.tB.enzotrlazolvl)ethvl) -Ν' - (2thiazolvl)thiourea
59.5 g benzotriazole (0.50 mol) was dissolved in 700 ml dimethylformamide. 160 g Sodium carbonate (1.5 mol) was added and then dropwise 73.5 g ethyl chloroacetate (0.60 mol). The stirred mixture was slowly heated to 40°C, and kept at that temperature for 17 h. The solvent was evaporated and the residue was extracted with ethyl acetate. GC showed one major and one minor product. The minor prouuc- ethyl-2-(2-oenzotriazoiyl) acetate was isolated by fractional crystallization from cold mixtures of ethanol and ethyl acetate.
7.1 g Of this minor product (40 mmol? was dissolved in 50 ml diethyl ether-tetrahydrofurane 1:1 and 1.5 g of lithium borohydride was added. The reaction mixture was stirred for 17 h at room temperature. The solvent was removed and replaced with 50 mi butanol. 5 ml Water was added and the temperature was slowly raised to about 50°C. After 4 h at this temperature the solvent was removed and the residue was partitioned between dichloromethane and
AP/P/ 9 5 / 0 0 7 2 3
AP Ο Ο Ο 3 8 8 « *
-3202 -ί2-benzotriazoly1) ethanol was isolated by crystallization from cold ethanol.
4.70 g of the 2-(2-benzotriazolyl)ethanol (28.3 mmol; was dissolved in 200 ml diethyl ether and
2.2£ g pyridine (28.8 nmol) was added. The mixture was cooled to -50°C, and 8.18 g triflic anhydride (29 mmol) was added. The mixture was removed from the cooling bath, and was allowed to reach room temperature. The mixture was filtered under dry 10 conditions and added to a cold -40°C solution of ca
150 ml ammonia in 50 ml diethyl ether. This mixture was allowed to reach room temperature, and ether was removed. 50 ml 2M HCl was added, and this mixture was washed with methylene chloride. The aqueous phase was made basic by addition of 50 ml 25 % sodium hydroxide and extracted with 3 x 25 ml methylene chloride. Evaporation of the solvent gave 2.10 g 2-(2berotr* 3’ 1' c*·hvlf12 9 mol! . This amine was used in the next step without further purification.
;.C 324 mg 2- (2-benzotriazolyl) ethylamine (2 mmol) and 420 mg 1-(2-aminothiazole)-1'-imidazole th±ocarbonyl (2 mrr.ol) were mixed in 3 ml acetonitrile. The mixture was slowly heated to reflux, and was then cooled tc allow the product to crystallize. Repeated crystallization from acetonitrile gave 234 mg pure N(2-( -2-benzctriazoly1) ethyl) Ν' - (2-thiazolyl) thiourea . -H-NMR (DM3O-dg): 4.5 2H (m) , 5.1 2H (m) , 6.75 IH (d) , 7.05 IH id!, 7.4 2H (m), 7.9 2H (m).
1;'C-NMK 47, 5b, 112, 119, 127, 145, 180.
'0 Araiysis 7;2Hi2NgS2: calculated C 47.35% H 3.97% N
27.61%; found: C 47.3% H 3.95% N 27.2%’
AP/P/ 95/00723
BAD ORIGINAL a
AP Ο Ο Ο 3 β 8
-32115
Example.. 3 cis/trans Ν-(2-(2-ethoxvDhenvlcvclopropanyl))-Ν' -(2pvridvl)thiourea
28.56 g methyl triphenylphosphonium bromide (80 mmol) in 500 ml tetrahydrofurane was cooled to -53°C. 50 ml n-Butyllithium in hexane (about 1.6 M, mmol) was added dropwise under stirring. The mixture was slowly warmed to room temperature, and kept there for two hours. The mixture was then cooled to -30°, and 12 g 2-ethoxybenzaldehyde (80 mmol) was added. The mixture was warmed to room temperature, and most of the solvent was removed and the residue was mixed with 400 ml ether and filtered. The solvent was evaporated and ethyl acetate was added to residue. The solution was passed through a pad of silica gel. This crude 2-ethoxystyrene was dissolved in 50 ml 1 ch ' step :
bane snd rhed as such in the next reaction
0.1 g Cul was added, and the mixture was heated to reflux temperature. 8.80 g Ethyl diazoacetate in 30 ml dichloroethane was then added dropwise over a period of 1 hour. GC-analysis showed the formation of two products xn a about 1:2 ratio. The two isomeric products were separated from other material by column chromatography (silica-gel, mixtures of hexane - ethyl acetate). This gave 3.lg of a cis/trans mixture of 2(2-ethoxyphenyl)-1-carboxyethyl cyclopropanes. The product mixture was hydrolysed in a refluxing mixture of 50 ml ethanol + 10 ml water + 4 g sodium hydroxide bad ORIGINAL
AP Ο Ο Ο 3 8 8
-3222 hours). The solvent was evaporated and the residue was made acidic with 100 ml 2M hydrochloric acid and extracted with 2 x 50 ml dichloromethane. The organic layers were dried and solvent was evaporated. 50 ml
Toluene was added followed by 6 g thionyl chloride.
The mixture was heated to 80°C for one hour and the solvent was then removed. 100 ml Acetone was added, the solution was cooled in an ice-bath and 4 g sodium azide in 20 mi water and 100 ml toluene was added after which the mixture was washed with 3 x 50 ml water. The organic layer was dried (Na2SO4), the solvent was evaporated and the residue was dissolved xn 100 ml dioxane. The dioxane solution was heated slowly to reflux, and kept at reflux 30 min. 25 ml
Concentrated hydrochloric acid was added and the mixture was refluxed for 2 hours. The solvent was removed and the residue was partitioned between 50 ml τ’^ronjetbapp and sn ml hydrochloric acid. The aqueous layer was made basic by the addition of 50 ml
25% sodium hydroxide solution, and extracted with 3 x ml dichloromethane. The dichloromethane solvent was evaporated and the residue was purified by column chromatography (silica-gel, mixtures of ethanol and etnyl acetate tc give about 1:1 mixture of cis/trans
/.ΐ 2 -(2-ethoxyphenyl) eye lopropyl-amines.
0.24 g 2-Aminopyridine ( 2.6 mmol) and 0.46 g tniocarbonylciimidazole (2.6 mmol) were stirred in 5 ml acetonitrile tor 2 hours. 0.41 g (2.6 mmol) of the mixture ct eyelopropylamines was added, and the reaccion mixture was heated slowly to 7C°C and stirred
AP/P/ 9 5 / 0 0 7 2 3
BAD ORIGINAL
AP Ο Ο Ο 3 8 8
-323at tha' temperature for 17 hours. The solvent was evaporated, and the titled product was isolated by column chromatography (silica-gel, mixtures of hexaneethyl acetate.
1H-NMR: 1.15-1.25 5H (m) , 2.50 IH (m), 3.42 0.55H (m),
3.3 0.45% im',, 4.0-4.1 2H (q) , 6.7-8.15 8H (m)
Example. 4.Q1
N-(2-(2-pvridvlethvl)) -Ν' - (2- (51C Chloropvridvl)) thiourea
1.73 g 2-Amino-5-chloropyridine (10 mmol) and 1.78 g thiocarbonyl diimidazole (10 mmol) were scirred for 2 hours in 15 ml acetonitrile. 1.47 g 2(2-Aminoethyl)pyridine (12 mmol) was added, and the mixture was stirred at room temperature for 2 hours.
The reaction mixture was then heated to 50°C and was stirred for 17 hours. Crystals were collected by f'lt-r-Qtior after cooling of the mixture.
Recrystallization from acetonitrile gave pure titled product.
iH-NMR (DMSO-dg): 3.2 2H (t), 4.1 2H (m) , 7.2-7.5 3H (m) , 7.8-8.0 2H (m), 8.2 IH (d), 8.7 IH (m), 18.0 IH is!, 11.5 IH (s)
Example 4.Q5
M-(2-(2-Pvridvlexbvl)!-Ν' -(2-(5-bromopvridvl)) thiourea
1.28 g 2-Amino-5-bromopyridine (10 mmol) and 1.7? g thiocarbonyl di imidazole (10 mmol) were stirred for 2 hours in 15 ml acetonitrile. 1.47g 2-(230 Amincethyl)pyridine <12 mmol) was added, and the
AP/P/ 9 5 / 0 0 7 2 3
AP Ο Ο Ο 3 8 8
-324The reaction mixture was then heated to 50°C and was stirred for 17 hours. Crystals were collected by filtration after cooling of the mixture.
Recrysf.aZ lization from acetonitrile gave pure titled
product.
<H-hMR .(DMSO-dg,’: 3.5 2H (t), 4.2 2H (m) , 7.2 2H (d),
7.3-8.1 3H (m), 8. .3 IK id), 8.6 IH (m) , 8 .9 IH id)
1C.9 IH (s), 11.4 IH (' t)
IC Example 406
N- (2- (2-pyrrdvlethvl))-N‘-(2-(5-nitropvridvl)) thiourea
1.39 σ 2-Amino-5-nitropyridine (10 mmol) was dissolved in 20 ml tetrahydrofurane. 0.68g (10 mmol) Sodium ethoxide (10 mmol) was added. The mixture was heated to 50°C and stirred for 30 minutes. The mixture was cooled, and most of the liquid was decanted from the formed red precipitate. The .Ll..,l -.3..e,. —P in .-u mi acetonitrile, and added to 1.78 g thiocarbonyl diimidazole in 10 ml acetonitrile. This mixture was stirred for 10 minutes at room temperature. 1.22 g 2-(2-Amino-ethyl)pyridine was added and the mixture was stirred for one hour. 1 ml Acetic acid was added, and the solvent was evaporated. The residue was washed with water.
.75 Repeated crystallizations from acetonitrile gave 1.28 g yellow crystals of the titled product.
1h-NKR (DMSO-dg): 3.1 2H 't), 3.2 2H (t), 7.2 IH (m),
7.? 3H (m) , 7.7 IH (m), 8.4 IH (m), 8.5 IH (m), 8.9 IH (d,
AP/P/ 95/00723
·) '·
BAD ORIGINAL A
AP Ο Ο Ο 3 8 8
-325Example -4.02 χΝ- (2- (2-pyridylethyl.))-Ν' -(2- (5me th,:.· ipyridyJ. LI thiourea
1.78 g thiocarbonyl diimidazole (10 mmol) and 1.5c g 2-amino-5-methyIpyridine (10 mmol) in 15 ml acetonitrile were stirred for 1 h at room temperature. 1.22 g 2- (2-Am.inoethyl)-pyridine was added. The mixture was stirred 1 h at room temperature, and then 17 h at 50°C. The mixture was cooled and crystals were collected by filtration. Recrystailization from acetonitrile gave 1.20 g pure titled product.
in-NMR (DMSO-dg): 2.2 3H (s), 3.1 2H (t), 4.0 2H (m), 7.0 IH (d), 7.2 IH (m), 7.3 IH (d), 7.6 IH (m), 7.7 IH (m), 7.8 IH (m), S.6 IH (m) 13C-NMR: 17.3, 36.3, 44.0, 112.1, 121.7, 123.5, 126.7, 136.6, 139.7, 144.6, 149.2, 151.8, 159.0, 179.2
Example 4Q8 (N-(2-(2-pyridylethyl))-Ν' -(2 - (5bromopvridvl)) thiourea HCl salt)
100 mg N-(2-(2-pyridylethyl))-Ν'-(2-(5bromopyndyl) ! thiourea (Example 405) was added to about 10 ml water. The suspension was heated to about 9C°C and pH was adjusted to about 3 by addition of hydrochloric acid. The titled product was isolated by freeze-drying.
-H-xNMR iD.HSO-d^!: 3.6 2H (t), 4.2 2H (m) . 7.2 2H (di. 7.9-8.1 oil (III! , 8.3 IH id), 8.6 IH (m) , 8.9 IH (d)
10.9 IH (si, 11.4 IH (t)
AP/P/ 9 5 / 0 0 7 2 3
BAD ORIGINAL fl
APO OO 0 8 8
-326Example 4QS, ;tl- (2- i2?-pyxidylet.hvlJ-) -ir -. 12^.15chloropvridvl)) thiourea HCl salt)
100 mg N-(2-(2-pyridylethyl))-Ν' - (2-(53 chlcropyridyl)) thiourea (Example 404) was added to above 10 mi water. The suspension was heated to about 90°C and pH was adjusted to about 3 by addition of hydrochloric acid. The titled product was isolated by freeze-dxying.
3-H-NMF. (DMSO-dg): 3.6 2H (t) , 4.2 2H (m), 7.3 IH (d) ,
S.0-3.2 3H (m,. 8.3 IH (m), 8.6 IH (m), 9.0 IH (m),
10.9 IH (s,, 11.4 IH ft).
Example 41Q
N-(2-(-2-Benzotriazolvl) ethyl)N‘-(2- (5bromopyridyl]) thiourea
356 mg Thiocarbonyl diimidazole (2 mmol) and 345 mg 2-amino-5-bromopyridine (2 mmol) in 2 ml aceconitriie were stirred for 1 h at room temperature.
?0 324 mg 2- (2-Benzotriazolyl)ethylamine (Example 402) (2 mmol) ‘-’as then added. This mixture was stirred for 10 min, and was then heated to reflux. After 20 min 5 ml more Eioetcnitnie and 3 ml dimethylformamide were added ro give a clear solution. The solution was <-··>··led an) the resulting precipitate was collected after centrifugation. Recrystallization from acercnitrile-dimethylformamide gave 310 mg of the pure l i ! I < 1 j ι . ί Ιι η η .
'DMSO-dg): 4.44 2H (m) , 5.15 2H (m) , 7.18 IH (d) , 7.56 2H (m) , 7.90 lH (d), 8.04 3H (m), 10.93 IH
AP/P/ 9 5 / 0 0 7 2 3
AP Ο Ο Ο 3 θ 8
-32713C-HMR: 44, 55, 114, 118, 118, 127, 142, 144, 146,
15/. 180 FPM
Example 411
Ν- ' 2 - (2,6-difluoro · 3-rae.Lhoxvpheny_lLethyl) -N’-(2-(5bromopyridyl)?thiourea
334 mg 2-(-2,6-difluoro-3ethoxyphenyi)ethylamine (Example 401) (mw 167, 2 mmo 1) ar.d 566 mg 1-(2-(510 iromopyridyl)thiocarbamoyl)imidazole (Example 392) (mw
223.15) (2 mmol) were mixed in 3 ml acetonitrile. The mixture was slowly heated to reflux, and was then cooled to crystallize. Repeated crystallization from acetonitrile gave 238 mg of the pure titled product.
1H-HNMR: (DMSO) 3.12 2K (t), 3.86 3H (s), 4.00 2H (m),
6.82 3H (m), 7.68-7.72 IH (m), 8.12 IH (d), 9.16 IH (s), 11.35 IH (s)
Example 412 z : N-(2-(3,4.5-trimethoxv)-benzvl)-Nz-(2thiazolvl) thiourea
The starting material 3,4,5tnmethoxybenzylamine was prepared by reduction of 3,4,5-trimethoxybenzonitrile with cobalt chloride and sodium borohydride, according to the general method described by L.S.Heinzman in J. Am. Chem. Soc., 104, p. 6801 (1930'.
3,4,5-trimethylbenzonitrile (965 mg, 5 mmole) and cobolt chloride (2.37 g, 10 mmole) were
AP/P/ 95/00723
ΑΡ Ο Ο Ο 3 8 e
-328added sodium borohydride (1.89 g, 50 mmole). After 3 nrs, the reaction mixture was filtered through Celite, and concentrated to small volume. It was then taken up in chloroform and extracted with IN HCl (100 ml).
The organic phase was discarded. The aqueous phase was basified with aqueous ammonia, and extracted with chloroform. The organic phase was dried over magnesium sulfate, and evaporated in vacuo to yield 3,4,5trimethoxybenzylamine (427 mg).
iH-NMR(CDCl3,d: 6.58 (s, 2H, TMPh), 3.85 (m, 6H, 2 x
MeO), 3.82 (s, 3H, MeO), 3.80 (m. 2H, CH2 ) .
The titled compound was prepared analogous to Example 105 .
iH-NMF. (CDCl3)d: 7.26 (d, IH, thiazole), 6.85 (d, IH, thiazole), 6.64 (s, 2H, TMPh,, 4.84 (d, J= 5.7Hz, 2H,
CH2! . 3.86 'm,6H, MeO), 3.85 (s, 3H, MeO).
--'C-NMR iCOCi3) a: i7'/ (C=S), 161 (thiazole), 153 (TMPh), 138 (TMPh), 137 (thiazole), 132 (TMPh), 111 (thiazole), 104 (TMPh), 61 (MeO), 56 (MeO), 50 (CH2).
Example 413 .2_-.rg.rmyl-3 - f luoropvridine
Dry ethyl ether (500 mL), n-BuLi (1.6 & in hexar.e, 62.5 mL, 0.1 mol), and dry 1,4diazabicycio[2.2.2loctane (DABCO) (11.56 g, 0.1 mol) were introduced into a 1 L fiask under a dry N2 stream at -60°C and the result ing cloudy solution was stirred for 1 hour' at -20°C. The mixture was then cooled to -75°C and an ethyl ether (50 mL) solution of 3-fluoropyridine (9.81 g, 0.1
AP/P/ 9 5/00723
APO 00 3 8 8
-329hours at -60°C. The mixture was recooled to -75°C, dry N, h’-dimethyl formamide (8.52 mL, 0.11 mol) dissolved in etr.yi ether (50 mL) was added dropwise and the mixture stirred for 2 hours at -75°C. Water (175 mL) was introduced slowly at -10°C, the aqueous layer extracted with ethyl acetate (5 x 2C0 mL), and the combined extracts ware dried over anhydrous sodium sulfate. Solvent removal produced a dark brown oil which after vacuum distillation and purification by chromatography on silica gel provided
4.4 σ (35%) cf the titled product as an off-white crystalline solid: mp 49-49°C;
IR (CHCI3, cm’1) 3071, 3020, 2873, 2842, 1720, 1588, 1461, 1441;
1H UMR (30C MHz, CDCI3) 5 10.21 (s, IH) , 8.62 (m, IH) ,
7.57 (m, 2H);
MS (FD) m/e 125 (M+);
UV (EtOH) 263nm (€=1551), 201nm (€=2188)
Example 414
2-Hydroxymethyl-3-f luoropyridine
A solution of 2-formyl-3-fluoropyridine (4.0 g, nvrol! and sodium borohydride (309 mg, 8 mmol) in absolute ethanol (40 mL) was stirred at O°C for 15 minutes and at room temperature for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride (5 mL) and filtered through diatomaceous earth to remove solids. The filtrate was evaporated and the resultant white solid was dissolved in ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (5 x 30 mL) and the combined extracts were dried over anhydrous sodium sulfate.
AP/P/ 9 5 / 0 0 7 2 3 bad ORIGINAL
AP000388
-330Solvent removal provided 3.78 g (93%) of the titled product as a pale yellow oil:
IR (CHCI3, οη*1) 3607, 3439, 3019, 1607, 1576, 1451, 1416, 1312, 1257, 1218, 1209, 1167, 1105, 1053, 857, 803;
:H NMR (300 MHz, CDCI3) δ 8.38 (m, IH,, 7.39 (m, lH), 7.26 im, IE), 4.83 (s, 2H) , 3.73 (br s, IH) ;
MS (FD) m/e 127 <M+);
UV (EtOH; 263nm (£=2796), 201nm (£=3651)
Anal. Calcd for CgHgFNO: C, 56.69; H, 4.76; N, 11.02. Found: C, 56.45: H, 4.97; N, 10.89
Example. ..415.
2.-xhlgxg.m,ethYl - 3-f lupippyridine.. hydrochloride
To a solution of 2-hydroxymethyl-3fluorcpyridine(3.43 g, 27 mmol) in dichloromethane (30 mL) cooled to -10°C was added neat thionyl chloride (4.4 mL, 60 mmcl) dropwise over 5 minutes. The resultant pale green solution was stirred at -10°C for 3 hours followed by evaporation to dryness to provide 4.66 g (95%) of the titled product as an off-white crystalline solid:
AP/P/ 9 5 / 0 0 7 2 3
IR (CHC13, cm1) 2984, 1732, 1551, 1470, 1452, 1333, 1286,
-J 73, 1237, 1219, 1208, 1193, 1094, 905, 863, 806;
1H NMR (300 MHz, CDCI3) δ 8.69 (m, IH) , 8.06 (m, IH) , 7.89
' m, , IH), 5. 09 !s, 2H);
MS ( FD) m/e 145 (M+ free base), 147 (M+2 free base)
Example 416 licvanemethvl-3-- fluoropvr idine A solution of 2-chloromethyl-3-fluoropyridine hydrochloride (4.85 g, 26.7 mmol) and potassium cyanide (3.47 g, 53.4 mmol) in methanol (50 mL) and water (20 mL)
BAD ORIGINAL
AP Ο Ο Ο 3 8 8
-331 was stirred at approximately 55°C for 17 hours. The resultant black solution was concentrated to an oil under reduced pressure, redissolved in ethyl acetate and water, and adjusted to pH 11.5 with solid sodium carbonate. The aqueous layer was salted with sodium chloride, extracted with ethyl acetate (7 x 40 mL), and the combined extracts were dried over anhydrous sodium sulfate. Solvent removal provided 3.6 g (99%) of (4) as a black solid:
IP. 'CHCI3, cm'1) 3019, 3011, 2977, 1708, 1603, 1578, 1454, 10 1412, 1259, 1222, 1219, 1215, 1161, 1097, 1047, 804; 1H NMR (3U0 MHz, CDCI3) δ 8.43 (m, IH) , 7.42 (m, IH), 7.33 (m,
IH). 3.97 (s, IH), 3.96 (s, IH); MS (FD) m/e 136 (M+); UV (EtOH! 263nm (€=3719), 203nm (€=3707)
Example 41?
2-aminoethyl-3-fluoroovridine
To a solution of 2-cyanomethyl-3-fluoropyridinein absolute ethanol (75 mL) and 5H hydrochloric acid (0.3 mL) was 3dded platinum oxide catalyst (0.64 g) and the mixture was hydrogenated at 60 psig for 1 hour in a Paar hydrogenation apparatus. Filtered off the catalyst, concentrated the filtrate under reduced pressure to a brown oil, dissolved the oil in water (40 mL) and ethyl acetate 10 mL) and adjusted to pH 0.9 with concentrated hydrochloric acid. Separated the layers, extracted the ethyl acetate layer with 1M HCl (1 x 10 mL), combined the acidic aqueous extracts and washed them with ethyl acetate ;4 x 30 mL). Adjusted the aqueous layer to pH 10.8, extracted with dichloromethane (6 x 30 mL), and the
Αροο Ο 388
-332Solvent removal provided 1.58g (70%) of the titled product as e brown oil:
IR (CHCls, cm-1) 2969, 2873, 1632, 1602, 1575, 1550, 1450, Ϊ414, 1359. 1246, 1219, 1212, 1203, 1169, 1093;
1h NMR (300 MHz, CDCI3) δ 8.31 (m, IH), 7.29 (m, IH), 7.13 (m, IH), 3.03 (m, 4H), 1.80 (br s, 2H) ;
MSiFDi m/e 140(M+);
Titration (66% DMF/H2O) pKa 9.56 x0 Examplel-f i2-15..-.chlprQlpYridylltlupcarbamQYll imidazole
A solution of 1,11-thiocarbonyldiimidazole ;4.95g, 23 mmol) and 2-amino-5-chloropyridine (3.28g, 25 mm.ol) in acetonitrile (75 mL) was stirred at room temperature for 23 hours. The resulting precipitate was collected by filtration to provide 3.42 g (57%) of the titled product:
IR (KBr. cm1) 3218, 3090, 1599, 1572, 1551, 1529, 1471,
1455, 1390, 1375, 1340, 1310, 1228, 1183, 1109, 1053, 939,
851;
3H NMR (300 MHz, DMSO-cfg) δ 8.58 (m, IH) , 8.25 (m, IH) ,
:.05 (br s, IH), 8.03 (m, IH), 7.65 (m, IH), 7.15 (d, J=8 Hz, IH) , 6.80 (s, IH);
MS (FAB) m/e 239 (M+l);
(Τ' -.EtOHi 205nm (£=15141), 273nm (£=14730), 226 nm (£=11407), 203 nm (£=16456).
Example 419
1..-1(2- [5-bromoIpvridvl)thiocarbamoylI imidazole
A solution of 1,1‘-thiocarbonyldiimidazole
AP/P/ 95/0072 5
AP Ο Ο Ο 3 8 8
-333nmcl) in acetonitrile (75 mL) was stirred at room temperature for 23 hours. The resulting precipitate was collected by filtration to provide 5.42 g (76%) of the titled product:
IR (KBr, cm’1) 3218, 3088, 1594, 1565, 1550, 1465, 1387,
1370, 1340, 1309, 1251, 1196, 1182, 1096, 1053, 938, 828; -K NMR (300 MHz, DMSO-dg) δ 8.57 (m, IH) , 8.30 (m, IH) , 8.15 im, IH), 8.03 (br s, IH), 7.75 (m, IH), 7.15 (d, J=8 HZ, IH), 6.80 (S, IH); MS (FAB) m/e 284 (M+l); UV (EtOH)
304nm (ε=13932), 274nm (£=13051), 230 nm (£=11098), 204 nm (£=17 821) .
Example.. 42,0.
N-f 2 - (2-f 3-f luoro Ipvridvl) ethvl ]-N‘D2- (515 bromo)pvridvllthiourea
A solution of 1-((2-(5bromo3pyridyl)thiocarbamoyl] imidazole (7) (1.42 g, 5 mmol) and 2-aminoethyl-3-fluoropyridine (5) (0.7g, 5 mmol) in N,N-dimethylformamide (20 mL) was stirred at 95°C for 3 hours. The reaction was cooled to room temperature, poured into ethyl acetate, and washed with water, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over anhydrous sodium sulfate, concentrated and the resultant solid was purified by chromatography on silica gel to provide 0.33 g (19%) of the titled product as a white solid: mp 184-187 °C;
IR (Kfar, cm’1) 3161, 3023, 1597, 1579, 1555, 1524, 1488, 1473, 1447, 1364, 1342, 1315, 1236, 1221, 1172, 1142, 1087,
AP/P/ 95/00723
AP Ο Ο Ο 3 8 8
-334NMR (300 MHz, DMSO-dg; δ 11.38 (m, 1Η) , 10.64 (s, 1Η) ,
S.41 (m, 1Η), 8.14 (d, J=2 Hz. IH) , 7.91 (m, IH), 7.63 (m, IH). 7.32 (m, IH), 7.06 (d, J = 9 Hz, IH), 4.01 (m, 2H), j.iO it, J = o Hz, 2H) ;
MS (FD: m/e 355 (M+), 357 (M-2,;
(EtOH) 305nm (£=13169), 273nm (£=25811), 201 nm (£---17 4 93 i .
Example 421
N- f 2 - (2 - f 3,- fluoro-l-Dvridyl) ethyl I tN12 -.15 chloro LgyridYl kthionrea
A solution of 1-((2-(5chloro,pyridyl)thiocarbamoyl] imidazole (2.39 g, 10 mmol) and 2-aminoethyl-3-fluoropyridine(1.4g, 10 mmol) in N,N15 dimet-hylformamide (25 mL) was stirred at 95 °C for 3 hours.
The reaction was cooled to room temperature, poured into e’-hvl nretate. and washed with water, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over anhydrous sodium sulfate, concentrated and the resultant solid was purified by chromatography on silica gel to provide 0.96 g (31%) of the titled product as an off-white solid:
zp 170-173 °C;
TR (KBr, cm-1) 3167, 3022, 1603, 1583, 1554, 1524, 1492,
1474, 1419, 1367, 1342, 1317, 1238, 1222, 1173, 1142, 1087,
835, 803;
-‘H NMR (3u0 MHz, DMSO-d6> δ 11.39 (m, IH), 10.65 (s, IH),
4S -in, XH) , 8.07 (d, J = 2 Hz, IH) , 7.31 (m. 111) , 7.63 (m, IH,,.7.33 (m, IH), 7.11 (d, J=9 Hz, IH), 4.01 im, 2H),
AP/P/ 9 5 / 0 0 7 2 3
AP Ο Ο Ο 3 8 8
-335MS (FD) m/e 310 (Μ*), 312 (M+2'. ;
UV (EtOH) 305nm (£=11338), 272nm (£=23394).
Example Λ2.2 (+) and (-) N-icis-2-phenylcvclopropvl)-S-a-methoxv phenvlacetamide
Ξ-α-methoxyphenylacetic acid (2.0 g, 12 mmol) was dissolved in dichloro-methane (100 ml) and oxalylchloride (1.36 mi, 16 mmol) was added together with 2 drops of N,N10 dimethylformamide. The solution was stirred under an atmosphere of nitrogen gas at ambient temperature for 120 minutes. The solvent and excess reagent were removed on a rotavapor. The oily residue was dissolved in 100 ml dichloromethane and D,L-cis-phenylcyclopropylamine (Example
202) (2.0 a, 15 mmol) in pyridine (5.0 ml) was added. The solution was stirred for 15 minutes and diethyl ether (200 mi) was added. The precipitate was filtered off and the solution was evaporated. The residual crystalline diascereoisomerical mixture was purified by flash20 chrcmathography by elution with ethyl acetate-toluenedichloroethane (1:2:2). The fractions containing the faster eluting product were evaporated to yield product A. The slower eluting fractions were evaporated to yield product E .
Z. J
A] ^H-NMR (35 mg in 0.6 ml CDCI3, 294 K) 0.99-1.06 (IH,
m) , 1.29-L.38 (IH, m) , 2.29-2.38 (IH, q) , 3.00 (3H, s), 3.07-3.17 (m), 4.41 (IH, s) , 6.3 (IH), 7.16-7.32 (10H, m).
A D/Pz 0 5 / 00723
BAD ORIGINAL fl
AP Ο Ο Ο 3 8 8
-33613C-NMF: 11.18, 21.83, 27.82, 57.11, 83.68, 126.34, 126.43, 126.06, 128.18, 128.26, 128.78, 136.15, 136.85, 171.75, 171.75.
calc for CigHigN: C 76.84 %, H 6.80 %, N 4.99%
Mp. 136.7-137.1°C
B. ^K-NMP. (same conditions as for A): 1.09-1.16 (IH, q) , 1.32-1 41 (IH, q), 2.24-2.38 (IH, q), 3.10-3.20 (4H, m) , 4.45, (IH, s), 6.4 (IH), 6.95-6.99 (2H, m) , 7.15-7.27 (7H,
m) .
13C-NMR: 10.69, 21.82, 27.85, 56.87, 83.63, 126.35, 126.87, 126.00, 128.13, 128.19, 128.83, 135.88, 136.54, 171.55.
Calc for C18H19N: C 76.84 %, H 6.80 %, N 4.99 %
Mp. 143.6-144.7°C.
Example 423 (-) cis-2-phenvlcyclopropvlamine Compound A (1.2 g) was refluxed in a mixture of water-dicxane-hydrcchloric acid conc.aq. (1:1:1) for 4 21 hours. The solution was diluted with water, washed with dichicromet'nane, basified with ammonium hydroxide (cone, aq.ι, extracted with dichloromethane, dried with sodium sulfate, filtered and evaporated to yield the titled pioduc’· as an oil.
]E-NMR CLCI3 δ ppm 0.8-0.9 (IH, CH2 , m), 1.1-1.2 (IH, CH2, mi , ,2.-2.1 (IH, PhCH, q) , 2.6-2.7 (IH, CHNH2, m) , 7.1-7.4
AP/P/ 95/00723
AP Ο Ο Ο 3 8 8
-337Example 424 (+) cis-2-phenvlcycloDropvlamine Compound Β (1.2 g) was refluxed in a mixture of water-dioxane-hydrochloric acid cone. aq. (1:1:1) for 4 5 hours. The solution was diluted with water, washed with dichloromethane, basified with ammonium hydroxide (cone, aq. ), extracted with dichloromethane, dried with sodiumsulfate, filtered and evaporated to yield the titled product as an oil.
1? i-H-NMR CDCI3 δ ppm 0.8-0.9 (IH, CH2, m) , 1.1-1.2 (IH, CH2,
m), 2.0-2.1 (IH, PhCH, q), 2.6-2.7 (IH, CHNH2, m)> 7.1-1.4 (5H, Ph).
D [a] = + 62.7° (C 1, CHCI3)
20
Example 425 (-i -N- (cis-2-DhenvicvclQDrQPvl·) -Nz-(5-chioropvrid-2-vl)thiourea (+)-N-cis-2-phenylcyclopropylamine (0.23 g, 1.7 mmol) from Example 424 was condensed with 1-(5-chloropyrid2-yl-thiocarbamoyl)-imidazole (0.4 g, 1.7 mmol) according tc the procedure of Example 372 to yield the titled product as crystals.
iH-NMR CDClj 0 ppm 1.2-1.3 (IH, m, CU2 > > 1.5-1.6 (IH, m,
Ch2) < 2.5-2.6 UH, q, PhCH), 3.7-3.8 (CJBN), 6.6-6.7 (IH, d, pyr?, 7 2-7.5 (7H, Ph, pyr), 8.9-9.0 (IH, NH), 10.8-10.9 (IE, NH)·
AP/P/ 9 5 / 0 0 7 2 3
BAD ORIGINAL
AP Ο Ο Ο 3 8 8
-338Μρ. 139.6-191.3°C.
D (a) = - 62.7° (C 1, CHCI3)
Example 426 i+V-N- {cls-2-phenvlcvclopropvl.) -Ν'-i5-chloropvrid-2-vl) thiourea (-5-N-cis-2-phenylcyclopropylamine (0.23 g, 1.7 10 mmol? from Example 423 was condensed with 1-(5-chloropyrid2-yl-thiocarbamoyl)-imidazole (0.4 g, 1.7 mmol) according to the procedure of Example 372 to yield the titled prodiuct as crystals.
I-H-NMR CDCI3 δ ppm 1.2-1.3 (1H, m, CH2) , 1.5-1.6 (1H, m, r5 C£2> . 2.5-2.6 (IH, q, PhCH), 3.7-3.8 (CHN) , 6.6-6.7 (1H, d, pyr), 7.2-7.5 (7H, Ph, pyr), 8.9-9.0 (IH, NH), 10.8-10.9 (IH, NH)·
Mp. 189.2-191.8°C.
D [a] = + 59.3° (C 1, CHCI3)
Example 427
-L-HN- (ciS--2^Pkenylgv.clQDrQnvllrN' - (5-bromopvrid-2-vl) 25 thiourea ( + )-N-cis-2-phenylcyclopropylamine from Example 424 and 2-amino-5-bromopyridine were reacted according to the procedures of Examples 93 and 94 using 2-amino-5bromopyridine instead of 2-aminothiazole, to give the titled product as crystals.
AP/P/ 9 5 / 0 0 7 2 3
BAD ORIGINAL ft
AP Ο Ο Ο 3 8 8
-339Ιη-NMR (CDC13): 1.19 - 1.26 <ro, 1Η), 1.47 - 1.55 (m, IH) , 2.52 ;q, In). 3.66 - 3.75 (m, IH), 6.66 (dd, IH), 7.27 7.41 im, 5H>, 7.17 (d, IH), 7.60 (dd, IH), 8.98 (broad s., IH), 10.88 (broad s., IH).
Mp = 192.0 - 193.0°C (a) = - 52.8° (C 1, CHCI3) .0
Example 428
- ν- (c;.s.-2-phenvlcyclPD£GDyU -Ν' - (5-bromopyrid-2-vl) thicurea (-)-N-cis-2-phenylcyclopropylamine from Example 423 and 2-amir.o-5-bromopyridine were reacted according to the procedures of Examples 93 and 94 using 2-amino-5broin'oyridir.e instead of 2-aminothj.azole, to give the titled product as crystals.
AP/P/ 95/00723
!h-NMR (CDCI3): 1.19 - 1.26 (m, IH), 1.47 - 1.55 (m, IH)
2.52 (q, IH), 3.66 - 3 .75 (m, IH), 6. 66 (dd, IH), , 7.27 -
7.41 (m, 5H), 7.47 id, IH), 7.60 (dd, IH), 8.98 (broad s
IH) , 10.88 (broad s.. IK) .
Mp = 195.5 - 196.5°C
D [a] = + 50° (C 1, CHCI3)
BAD ORIGINAL

Claims (25)

  1. 340
    The claims defining the invention are as follows:
    1. A method for inhibiting the replication of HTV which «compound contracting a compound of the formula below
    Rz-N-I-N-Ri (IA)
    5 in which Rj is a stable, saturated or unsaturated, substituted or unsubstiiuthd. 3 tc .·, raembered crganic monocyclic ring having 0 to 4 hetero atoms selected from S, O. N. or Rj is a stable, saturated or unsaturated, substituted or unsubstituted, 7 to 10 inemlxn. otganic oicyclic ring having 0 to 5 hetero atoms selected from S, O, and N;
    R2 is a group of the formula
    Re R?
    U-i,0 kA» wherein R5 is Rj as defined above; or R5 is a group of the formula (Rio)y-X· wherein y is 1 or 2; X is N, S, 0 and R10 is Rj as defined; or R|q is hydrogen, C,-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; or R5 is hydrogen, halo, cyano, carboxy, amino, is thio, hydroxy, Cj-C4 alkoxy, Cj-C6 alkyl, C2-C8 alkenyl, C2-Cb alkynyl, or C2-C8 alkenoxy;
    R$, R7, R8, and Rg are independently Cj-Cg cycioalkyl, hydrogen, Cj-C* alkyl, -Ik-uyi, C2-c6 aikynyl, halo, amino, nitro, cyano, Cj-Cj alkoxy, hydroxy, carboxy, hydroxymethyl, aminomethyl, carboxymethyl, Cj-C4 alkylthio, Cj-C4 20 alkanoyloxy, carbamoyl, or a halo substituted Cj-C6 alkyl; or two of wh'ch, aiong with the carbons to which they are attached, combine to form a stable, saturated or unsaturated, substituted or unsubstituted, 3 to 7 membered organic monocyclic ring having 0 to 4 hetero atoms selected from S, 0, or N; or Rg and Rg, or R7 and Rg, along with the carbon to which they are attached, form a stable, saturated or unsaturated, 25 substituted or unsubstituted, 3 to 7 membered organic monccyclic ring having 0 te 4 hetero atoms selected from S, 0, or N;
    R3 and R4 are independently hydrogen, hydroxy, Cj-C6 alkyl, C2-Cb alken/i. C2-C6 alkynyl, amino, cyano, nitro, Cj-C5 alkoxy, carboxy, hydroxy nv hyl, ammomethyl, carboxymethyl, Cj-C4 alkylthio, Cj-C4 alkanoyloxy, halo substituted sc (Cj-C6)dlkyl, or carbamoyl; or salts thereof, with HIV.
    ΛΟ/Ρ/ 9 5 / 0 0 7 2 3
  2. 2. The method of claim 1 wherein R3, R4, R$, R7, R8, and Rg are all hydrogen.
  3. 3. The method of claim 1 or 2 wherein R5 is phenyl, substituted phenyl, naoluhyl, substituted naphthyl, pyridyl, substituted pyridyl, or cyclohexenyl.
  4. 4. The method of any one of claims 1 to 3 wherein Rj is thiazolyl, substituted 35 thiazolyl, benzothiazolyl. substituted benzothiazolyl, pyrazinyl, substituted pyrazinyl.
    bad original
    APO 0 0 388
    341 pyridyl, substituted pyridyl, pyridazinyl, substituted pyridazinyl, thiadiazuly!, oi substituted thiadiazolyl.
  5. 5. The method of any one of claims 1 to 4 wherein said compound is N-(2-(2pyridyl)ethyl]-N'-[2-(5-bromo)pyridyl]thiourea and its hydrochloride salt.
    5
  6. 6. A method for treating or inhibiting HIV in a human requiring such treatment or inhibition, comprising administering to said human an effective amount of a compound as defined in any one of claims to 1 to 5.
  7. 7. A method for treating or inhibiting AIDS in a human requiring such treatment or inhibition, comprising administering to said human an effective amount of a compound io as defined in any one of claims 1 to 5.
  8. 8. The method of any one of claims 1 to 7 further comprising also administering at least one other therapeutic agent to said human.
  9. 9. The method of claim 8 wherein said agent is selected from ddl, ddC, or AZT.
  10. 10. A compound of the formula IA as defined in claim I, wherein is Rg and R7 are independently C3-Cg cycloalkyl, hydrogen, Cj-C6 alkyl, C2-C6 alkenyl. C2-C6 alkynyl, halo, amino, nitro, cyano, Cj-C5 alkoxy, hydroxy, carboxy, hydroxymethyl, aminomethyl, carboxymethyl, Ct-C4 alkylthio, Cj-C4 alkanoyloxy, carbamoyl, or a halo substituted Cj-Cg alkyl;
    Rg and R9, along with the carbons to which they are attached, combine to form a
    2c stable, saturated or unsaturated, substituted or unsubstituted, 3 to 7 membered organic r:.z:.Living 0 :c ·! heic.o atoms selected from S, 0, or N, with the proviso that the compound is not
    Τ' nzp/ 0 5 / Π n 7 2 Λ , or salts thereof.
    25
  11. 11. The compound of claim 10 wherein Rj is thiazolyl, substituted thiazolyl.
    pyridyl, substituted pyridyl, pyridazinyl, substituted pyridazinyl, pyrazinyl, or substituted pyrazinyl; R5 is pyridyl, substituted pyridyl, phenyl, or substituted phenyl; and R8 and R9, along with the carbons to which they are attached form cyclopropyl.
  12. 12. The compound of claim 10 or 11 wherein the compound is N-(2-cis30 phenylcyclopropyl)-N'-2-(thiazolyl)thiourea.
  13. 13. The compound of claim 10 or 11 wherein said compound is selected from: N-(2-ci$-phenylcyclopropyl)-N’-[2-(5-bromo)pyridyl]thiourea N-(2-cis-phenylcyclopropyl)-N'-{2-(5-chloro)pyridylllhiourea N-[2-fcis-2-pyridyl)cyclopropyl]-N'-[2-(5-bromo)pyridy,]thiourea
    35 N42-(cis-2-pyridyl)cyclopropyll-N'-[2-(5-chloro)pyridyllthiourea
    BAD ORIGINAL
    APO00388
    342
    N-[2-<cis-2-{6-fluoro)pyridyl)cyclopropyl]-N’-[2-(5-brcmo)pyridylJthicurea
    N-[2-(cis-2-(6-fluoro)pyridyl)cyclopropyl]-N,-l2-(5-chloro)pyridyIJthiourea
    N-(2 -(cis-2-(6-methoxy)pyridyl)cyclopropyll-N'’[2-{5-bromo)pyridyI]thiourea
    N-(2-(cis-2-{6-methoxy)pyridyl)cyclopropyl]-N'-[2-(5-chloro)pyridyl]thiourea 5 N-[2-(cis-2-(6-ethoxy)pyridyl)cyclopropyl]-N,-(2-(5-bromo)pyridyIJthiourea
    N-[2-{cis-2-(6-ethoxy)pyridyl)cycIopropyl]-N'-[2-(5-chloro)pyridyl]thiou-ea; and salts thereof.
  14. 14. A compound of the formula IA as defined in claim 1 wherein R| is cyclo (C3-Cg)alkyl, cyclo (C3-Cg) alkenyl; isothiazolyl, substituted isothiazolyi, tetrazolyl, ό substituted tetrazolyl, triazolyl, substituted triazolyl, pyridyl, substituted pyridyl, imidazolyl, substituted imidazolyl, naphthyl, substituted naphthyl, benzoxazoly., substituted ben2oxazolyl, benzimidazolyl, substituted benzimidazolyl, thiazolyi, substituted thiazolyl, oxazolyl, substituted oxazolyl, benzothiazolyl, substituted benzothiazolyl, pyrazinyl, substituted pyrazinyl, pyridazinyl, substituted pyridazinyl, is thiadiazolyl, substituted thiadiazolyl, benzotriazolyl, substituted benzotriazolyl, pyrroiyl, substituted pyrroiyl, indolyl, substituted indolyl, benzothienyl, substituted benzothienyl, thienyl, substituted thienyl, benzofuryl, substituted benzofuryl, furyl, substituted furyl, quinolinyl, substituted quinolinyl, isoquinolinyl, substituted isoquinolinyl, pyrazolyl, and substituted pyrazolyl;
    2c R2 to R5 are as defined in claim I; and
    Rg, R7, R8, and R9 are independently C3-Cg cycloalkyl, hydrogen, Cg alkyl, ««ikeuyl, C2-Cg alkynyl, halo, amino, nitro, cyano, C1-C5 alkoxy, hydroxy, carboxy, hydroxymethyl, aminomethyl, carboxymethyl, Cj-C4 alkylthio, Cj-C4 alkanoyloxy, carbamoyl, or a halo-substituted CrC6 alkyl; or Rg and R8, or R7 and R9, 25 along with the carbon to which they are attached, form a stable, saturated or unsatuiated. substituted or unsubstituted, 3 to 7 membered organic monocyclic ring having 0 ω 4 hetero atoms selected from S, 0, or N, with the proviso that the substituents or compound are not the following:
    -CH2-CH2- (I)
    R2 = where Rg and R<. may be hydrogen, Cj-C4 alkyl, trifluoromethyl, phenyl or substituted phenyl; baD ORIGINAL
    ΑΡ Ο Ο Ο 3 8 8
    Ό
    343 where Rj may be hydrogen, halogen, hydroxy, Cj-Cg alkyl, or Cj-Cg alkoxy;
    (V)
  15. 15. The compound of claim 14 wherein R3, R4, R$, R7, Rg, and Rg are all hydrogen.
  16. 16. The compound of claim 14 or 15 wherein R5 is phenyl, substituted phenyl,
    10 pyridyl, substituted pyridyl, or cyclohexenyl.
  17. 17. TLw .Ciupuuuu 01 any one of claims 14 to 16 wherein Rj is pyridyl, substituted pyridyl, thiazolyl, substituted thiazolyl, benzothiazolyl. substituted benzothiazolyl, thiadiazolyl, substituted thiadiazolyl, pyrazinyl, substituted pyrazinyl, pyridazinyl, or substituted pyridazinyl.
    15
  18. 18. The compound of any one of claims 14 to 16 wherein Rj is pyridyl, fluoropyridyl, chloropyridyl, bromopyridyl, cyanopyridyl, methylpyridyl, ediylpyridyl, trifluoromethylpyridyl, dimethylpyridyl, thiazolyl, fluorothiazolyl, chlorothiazolyl, bromothiazolyl, methylthiazolyl, ethylthiazolyl, (nitrophenyl)thiazolyl, trifluoromethylthiazolyl, dimethy Ithiazoly I, cyanothiazolyl, pyridylthiazolyl,
    20 benzothiazolyl, (fluorobenzo)thiazolyl, fluoropyrazinyl, chloropyrazinyl, bromopyrazinyl, cyanopyrazinyl, methylpyrazinyl, ethyl pyrazinyl, trifluoromethylpyrazinyl.
    dimethy lpyrazinyl, pyridazinyl, fluoropyridazinyl, chloropyridazinyl, bromopyric’azinyl, cyanopyridazinyl, methylpyridazinyl, ethylpyridazinyl, trifluoromethylpyridazinyl dimethy lpyridazinyl;
    25 R5 is pyridyl, substituted pyridyl, cyclohexenyl, naphthyl, phenyl, or phenyl substituted 1-4 times by methoxy, ethoxy, bromo, methyl, fluoro, chloro, azido, and combinations thereof;
    R6 and Rg are independently hydrogen or C,-Cg alkyl; and salts thereof.
    U~>
    a·)
    0i c
    BAD ORIGINAL A
    APO 00 3 8 8
    AD/P' 95/00723
    344
  19. 19. The compound of any one of claims 14 to 18 wherein said compound is selected from;
    N-(2-(2-methoxyphcnyl)ethyI)-N'-[2-(4-cyano)thiazolylJthiourea N-(2-(2-methoxyphenyl)ethyl)-N,-[2-(4-trifluoromethyl)thiazolyl]thiourea 5 N-(2-(2-methoxyphenyl)ethyl)-N'-f2-(4-ethyl)thiazolyllthiourea N-(2-(2-methoxyphenyl)ethyl)-N'-[2-(5-bromo)pyridyl]thiourea N-(2-(2-methoxyphenyl)ethyl)-N'-[2-(5-chloro)pyridyl]thiourea N-(2-(3-methoxyphenyl)ethyl)-N’-[2-(4-cyano)thiazolyl]thiourea N-(2-(3-methoxyphenyl)ethyl)-N'-12-(4-trifluoromethyl)ihiazolylJihiourea io N-(2-(3-methoxyphenyl)ethyl)-N'-(2-(4-ethyl)thiazoly!]thiourea N-fl-fS-methoxyphenyOethylJ-N'-p-iS-bromoJpyridylJthiourea N-(2-(3-methoxyphenyI)ethyl)-N'-[2-(5-chloro)pyridyl]thiourea N-(2-(2-ethoxyphenyl)ethyl)-N'-[2-(5-bromo)pyridyl]thiourea N-(2-(2-ethoxyphenyl)ethyl)-N,-[2-(5-chloro)pyridyl]thiourea 15 N-(2-(2,6-difluorophenyI)ethyl)-N'-{2-(4-cyano)thiazolyl]ihiourea
    N-(2-(2.6-difluorophenyl)ethyl)-N'-(2-(4-trifluoromethyl)thiazolyl]thiourea N-(2-(2,6-difluorophenyl)ethyl)-N’-[2-(4-ethyl)thiazolyl]thiourea N-(2-(2,6-difluorophenyl)ethyl)-N’-(2-(5-bromo)pyridyl]thiourea N-(2-(2,6-difluorophenyl)ethyI)-N'-[2-(5-chloro)pyridyl]thiourea 20 N-(2-(2,6-difluorophenyl)ethyl)-N'-f2-(5-bronio)pyrazinyI]thiourea
    N-(2-(2,6-difluorophenyl)ethyl)-N,-[(3-(6-chloro)pyridazinyl)]thiourea N-f2-<2’fluoro-6-methoryph^ry’}cihyl)-N'-(2-(5-biOmo)pyridyl]thiourea N-(2-(2-fluoro-6-methoxyphenyl)ethyl)-N'-(2-(5-chloro)pyridyl]thiourea N -(2-(2-chloropheny l)ethy 1)-N ’-(2-(4-cyano)thiazolyl]thlourea 26 N-(2-(2-chloropheny!)ethyl)-N'-[2-(4-ethyl)thiazolyl]thiourea N-(2-(2-chlorophenyl)ethyI)-N'-[2-(5-bromo)pyridyl]thiourea N-(2-(2-chlorophenyl)ethyl)-N'-[2-(5-chloro)pyridyl]thiourea N-(2-(3-chJorophenyl)ethyl)-N'-[2-(4-cyano)thiazolyl]thiourea N-(2-(3-chlorophenyl)ethyl)-N’-[2-(4-ethyl)thiazoly IJthiourea 30 N-(2-(3-chlorophenyl)ethyl)-N ’ -[2-(5-bromo)pyridyl]thiourea
    N-(2-(3-chloropheny l)ethy 1)-N' -12-(5-chloro)pyridyl]thiourea N-(2-( l-cyclohexenyl)ethyl)-N'-[2-(4-cyano)thiazoly IJthiourea N -(2-( 1 -cyc!ohcxcnyl)ethyl)-N '-[2-(4-trifluoromethyl)thiazoly IJthiourea N-(2-( 1 -cy clohexeny I)ethyl)-N' -[2-(4-etliyl)thiazolyl)thiourea 35 N-(2-(l-cyclohexenyl)ethyl)-N'-[2-(5-bromo)pyridyl]thiourea N-(2-(l -cy clohexeny l)e thy 1)-N ‘-[2-(5-chlorojpyridy IJthiourea N-(2-(l-cyclohexenyl)ethyl)-N,-[(3-(6-chloro)pyridazinyl)]thiourea N-(2-(2,5-dimethoxyphenyl)ethyl)-N’-(2-(5-chloro)pyrazmylJthiourea N-(2-(2,5-dimethoxyphenyl)ethyI)-N’-[2-(5-bromo)pyrazinyl]thiourea BAD ORIGINAL
    40 N-i2-(2-pyridyl)ethyl]-N'-[2-(5-brorno)pyridyl]thiourea u
    ~~ AP 0 0 0 3 8 8
    345
    N-(2-(2-pyridyl)ethyl]-N’-{2-(5-chloro)pyridylJthiourea
    N-[2-(2-pyridyl)ethyl]-N'-[2-(5-trifluoroinethyl)pyridyl]thiourea
    N-[2-(2-pyridyl)ethyl]-N,-{2-(5-cthyl)pyridyl]thiourea
    N-(2-(2-pyridyl)ethyl]-N'-(2-(5-methyl)pyridyljthiourea s N-[2-(2-(6-methoxy)pyridyl)ethyl]-N'-f2-(5-bromo)pyridylJthiourea N-{2-(2-(6-methoxy)pyridyl)ethyIJ-N'-l2-(5-chloro)pyridyl]thiourea N-[2-(2-(G-elhoxy)pyridyl)eLliyIJ-N'-12-(5-bruiiio)pyridyl]iJiiourea N-(2-(2-(6-ethoxy)pyridyl)etliyIl-N'-(2-(5-chloro)pyridy!Jthiourea N-i2-(2-(6-fluoro)pyridyl)ethyIl-N'-(2-(5-bromo)pyridyl)lhiourea io N-[2-(2-(6-fluoro)pyridyl)ethylJ-N’-(2-(5-chloro)pyridyl]thiourea N-[2-(2-(3-fluoro)pyridyl)ethyl]-N'-(2-(5-bromo)pyridyIJthiourea N-[2-(2-(3-fluoro)pyridyl)ethyl]-N'-[2-(5-chloro)pyr!dyl]thiourea N-[2-(2-(6-chloro)pyridyl)ethyl3-N'-[2-(5-bromo)pyridyl]thiourea N-[2-(2'(6-chIoro)pyridyl)ethyll-N’-I2-(5-chloro)pyridyl]thiourea is N-[2-(2-(3-methoxy-6-fluoro)pyridyl)ethyl]-N'-[2-(5-bromo)pyridyJ]thiourea N-[2-(2-(3-methoxy-6-fluoro)pyridyl)ethylJ-N’-[2-(5-chloro)pyridylJthioureu N-[2-(2-(5-ethoxy-6-fluoro)pyridyl)ethyl]-N' -[2-(5-bromo)pyridyl]thiourea N-[2-(2-(5-ethoxy-6-fluoro)pyridyl)ethyl]-N’-[2-(5-chloro)pyridyl]thiourea N-[2-(2-(3-ethoxy-6-fluoro)pyridyl))ethyl]-N'-(2-{5-bromo)pyridyl]thiourea
  20. 20 N-(2-(2-(3-ethoxy-€-fluoro)pyridyl)ethyl]-N'-[2-(5-cWoro)pyridyl]thiourea Ν [2 (2 (3,v-uinuoro)pyndyOethyiJ-N'-f2-(5-bromo)pyridyl]thiourea N-[2-(2-(3,6-difluoro)pyridyl)ethyl]-N'-[2-(5-chloro)pyridyl]thiourea N-[2-(2,6-difluoro-3-methoxyphenyl)ethyI]-N'-[2-(5-bromo)pyridyJ]Uuourea; and salts thereof.
    25 20. N-[2-(2-pyridyl)ethyl]-N'-[2-(5-bromo)pyridyl]thiourea or its hydrochloride salt.
  21. 21. A pharmaceutical formulation comprising a compound as defined in any one of claims 10 to 20 associated with one or more carriers, excipients or diluents therefor.
  22. 22. The pharmaceutical formulation of claim 21 further comprising at least one
    30 other therapeutic agent.
  23. 23 The pharmaceutical formulation of claim 22 wherein said agent is ddl, ddC or
    AZT.
    AP/P/ 9 5 / 0 0 7 2 3
    BAD ORIGINAL 4
    APO 0 0 3 8 8
    346
  24. 28. A method for treating or inhibiting HIV in a human requiring such treatment or inhibition, comprising administering to said human an effective amount of a compound of claim 24 or a pharmaceutical formulation of claim 26.
  25. 29. A method for treating or inhibiting AIDS in a human requiring such treatment s or inhibition, comprising administering to said human an effective amount of a compound ol claim 24 or a pharmaceutical formulation ol claim 26.
APAP/P/1995/000723A 1991-08-02 1992-07-30 Inhibition of the replicateion of HIV and related viruses using thiourea derivative compounds or salts thereof. AP388A (en)

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