IE48426B1 - Novel aminothiazoles - Google Patents
Novel aminothiazolesInfo
- Publication number
- IE48426B1 IE48426B1 IE1069/79A IE106979A IE48426B1 IE 48426 B1 IE48426 B1 IE 48426B1 IE 1069/79 A IE1069/79 A IE 1069/79A IE 106979 A IE106979 A IE 106979A IE 48426 B1 IE48426 B1 IE 48426B1
- Authority
- IE
- Ireland
- Prior art keywords
- compound
- phenyl
- hydrogen
- formula
- carbon atoms
- Prior art date
Links
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical class NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 title description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 89
- 150000003839 salts Chemical class 0.000 claims abstract description 23
- 239000002253 acid Substances 0.000 claims abstract description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 33
- 239000001257 hydrogen Substances 0.000 claims description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims description 28
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 17
- 125000004432 carbon atom Chemical group C* 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 16
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 15
- -1 monosubstituted phenyl Chemical group 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 125000001246 bromo group Chemical group Br* 0.000 claims description 9
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 9
- 125000001153 fluoro group Chemical group F* 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 7
- 125000001544 thienyl group Chemical group 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- LIGACIXOYTUXAW-UHFFFAOYSA-N phenacyl bromide Chemical compound BrCC(=O)C1=CC=CC=C1 LIGACIXOYTUXAW-UHFFFAOYSA-N 0.000 claims description 5
- 239000007858 starting material Substances 0.000 claims description 5
- 206010061218 Inflammation Diseases 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 230000004054 inflammatory process Effects 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 4
- RXDYOLRABMJTEF-UHFFFAOYSA-N 2-chloro-1,2-diphenylethanone Chemical compound C=1C=CC=CC=1C(Cl)C(=O)C1=CC=CC=C1 RXDYOLRABMJTEF-UHFFFAOYSA-N 0.000 claims description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- 230000007812 deficiency Effects 0.000 claims description 2
- 201000010099 disease Diseases 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 2
- 238000011065 in-situ storage Methods 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 1
- 229910052794 bromium Inorganic materials 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000003472 neutralizing effect Effects 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 16
- UXZPFPLPTODLCU-UHFFFAOYSA-N 4,5-diphenyl-n-(2-phenylethyl)-1,3-thiazol-2-amine Chemical compound N=1C(C=2C=CC=CC=2)=C(C=2C=CC=CC=2)SC=1NCCC1=CC=CC=C1 UXZPFPLPTODLCU-UHFFFAOYSA-N 0.000 abstract description 2
- JUGUBOQRAJASOS-UHFFFAOYSA-N 4-(4-fluorophenyl)-n-(thiophen-2-ylmethyl)-1,3-thiazol-2-amine Chemical compound C1=CC(F)=CC=C1C1=CSC(NCC=2SC=CC=2)=N1 JUGUBOQRAJASOS-UHFFFAOYSA-N 0.000 abstract description 2
- NTUXEUGLSZFNPX-UHFFFAOYSA-N 5-methyl-4-phenyl-n-(2-phenylethyl)-1,3-thiazol-2-amine Chemical compound N=1C(C=2C=CC=CC=2)=C(C)SC=1NCCC1=CC=CC=C1 NTUXEUGLSZFNPX-UHFFFAOYSA-N 0.000 abstract description 2
- MFBJXMMGIRSWAP-UHFFFAOYSA-N 4-phenyl-n-(thiophen-2-ylmethyl)-1,3-thiazol-2-amine Chemical compound C=1C=CSC=1CNC(SC=1)=NC=1C1=CC=CC=C1 MFBJXMMGIRSWAP-UHFFFAOYSA-N 0.000 abstract 1
- WEEYMMXMBFJUAI-UHFFFAOYSA-N fanetizole Chemical compound N=1C(C=2C=CC=CC=2)=CSC=1NCCC1=CC=CC=C1 WEEYMMXMBFJUAI-UHFFFAOYSA-N 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 48
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- UMGDCJDMYOKAJW-UHFFFAOYSA-N aminothiocarboxamide Natural products NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 8
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- OFVGPHQYOCKLLM-UHFFFAOYSA-N 2-phenylethylthiourea Chemical compound NC(=S)NCCC1=CC=CC=C1 OFVGPHQYOCKLLM-UHFFFAOYSA-N 0.000 description 4
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- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
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- OCIDXARMXNJACB-UHFFFAOYSA-N n'-phenylethane-1,2-diamine Chemical compound NCCNC1=CC=CC=C1 OCIDXARMXNJACB-UHFFFAOYSA-N 0.000 description 1
- HKHXNMWREYJWGY-UHFFFAOYSA-N n-(furan-2-ylmethyl)-5-methyl-4-phenyl-1,3-thiazol-2-amine;hydrobromide Chemical compound Br.N=1C(C=2C=CC=CC=2)=C(C)SC=1NCC1=CC=CO1 HKHXNMWREYJWGY-UHFFFAOYSA-N 0.000 description 1
- JKOBOYCYCFKVJC-UHFFFAOYSA-N n-benzhydryl-1,3-thiazol-2-amine Chemical class N=1C=CSC=1NC(C=1C=CC=CC=1)C1=CC=CC=C1 JKOBOYCYCFKVJC-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940117803 phenethylamine Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 description 1
- 229940116357 potassium thiocyanate Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- FKKJJPMGAWGYPN-UHFFFAOYSA-N thiophen-2-ylmethanamine Chemical compound NCC1=CC=CS1 FKKJJPMGAWGYPN-UHFFFAOYSA-N 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
-
- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
- F16B—DEVICES FOR FASTENING OR SECURING CONSTRUCTIONAL ELEMENTS OR MACHINE PARTS TOGETHER, e.g. NAILS, BOLTS, CIRCLIPS, CLAMPS, CLIPS OR WEDGES; JOINTS OR JOINTING
- F16B15/00—Nails; Staples
- F16B15/0023—Nail plates
- F16B2015/0076—Nail plates with provisions for additional fastening means, e.g. hooks, holes for separate screws or nails, adhesive
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- Chemical & Material Sciences (AREA)
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- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
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- Engineering & Computer Science (AREA)
- Pain & Pain Management (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
A series of 2-aryl aminothiazoles and the pharmaceutically acceptable acid addition salts thereof having anti- antiflammatory and immune regulant activity are disclosed. Preferred compounds include 2- phenethylamino-4-phenyl-thiazole, 2- phenethylamino-4,5-diphenyl- thiazole, 5-methyl-2-phenethylamino- 4-phenyl-thiazole, 2-thenylamino-4- phenyl-thiazole and 2-thenylamino-4- (p-fluorophenyl)thiazole.
Description
This invention relates to novel substituted aminothiazoles useful for relieving inflammatory conditions and as immune regulants.
A number of compounds have been known in the art to be 5 useful as anti-inflammatory agents, for example the cortico steroids, phenylbutazone, indomethacin and various 3,4-dihydro4-OXO-2H-1,2-benzothiazine-4-carboxamide-l,1-dioxides, such as those disclosed in United States Patent No. 3,591,584. Accordingly, these compounds have been of therapeutic value in the treatment of arthritic and other inflammatory conditions such as rheumatoid arthritis. Such conditions have also been treated by administration of immunoregulatory agents, such as levamisole, as described for example in Arthritis Rheumatism, 20, 1445 (1977) and Lancet, 1, 393 (1976). In efforts to find new and improved therapeutic agents for the treatment of these conditions, it has now been found that the novel aminothiazoles of the present invention have a particularly desirable combination of pharmacological properties, namely that they are active both as anti-inflammatory agents and as regulants of the immune response in the body. Accordingly, they are of particular value in the treatment of rheumatoid arthritis and other conditions where relief of the inflammation and regulation of the body immune response is desired. Thus according to the invention there are provided novel compounds of the formula:
and the pharmaceutically acceptable acid addition salts thereof, wherein R^ is:
z
-CH \
X
-(ch„) ) -X, -CH„-CH_-NH-X or -(CH.) Y, wherein X is 2 2 n 2 2 2 m phenyl optionally monosubstituted with alkyl of 1 to 3 carbon atoms, hydroxy, alkoxy of 1 to 3 carbon atoms, chloro, bromo, or fluoro; Y is thienyl or furyl each being optionally monosubstituted with alkyl of 1 to 3 carbon atoms, chloro, bromo or fluoro; n is 2; m is 1 or 2? R^ is phenyl, thienyl or monosubstituted phenyl, said substituent being alkyl of 1 to 3 carbon atoms, hydroxy, alkoxy of 1 to 3 carbon atoms, chloro, bromo or fluoro; and R^ is hydrogen, alkyl of 1 to 3 carbon atoms, phenyl or monosubstituted phenyl, said substituent being alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, chloro, bromo, or fluoro.
Preferred substituents for R^ are phenyl and p-fluorophenyl and for R3 are hydrogen and phenyl.
A preferred group of compounds is that wherein R^ is
-(CH„) -X where n is 2. Most preferred are those compounds 2 n wherein X is phenyl or p-methoxy phenyl, R2 is phenyl or pfluorophenyl, R3 is phenyl, methyl or hydrogen, including 2phenethylamino-4-phenyl-thiazole, 2-phenethylamino-4,5-diphenyl-thiazole and 2-phenethylamino-5-methyl-4-phenyl-thiazole.
A further group of interest is that wherein R^ is -(CH2)ni-Y, especially where m is 1. Preferred groups for Y are thienyl and furyl especially those compounds where R2 is
8 12 6
- 4 phenyl or ρ-fluorophenyl and R3 is hydrogen, methyl and phenyl.
Yet a further group of compounds are those wherein /X is -CH , preferred compounds being those where X is phenyl,
R^ is phenyl and R3 is hydrogen or phenyl.
Another group of compounds of interest are those wherein R^ is -C^-CH^-NH-X, especially those compounds where X is phenyl, R^ is phenyl and R3 is hydrogen.
Also embraced by the present invention are pharmaceuti10 cal compositions comprising a novel substituted aminothiazole of this invention, as described above herein, or a pharmaceutically acceptable acid addition salt thereof, together with a pharmaceutically acceptable carrier or diluent. Preferred pharmaceutical compositions are those containing the preferred compounds described above and most preferably containing 2phenethylamino-4-phenyl-thiazole, 2-thenylamino-4-(p-fluorophenyl)-thiazole or 2-(p-methoxyphenethylamino)-4-(ρ-fluorophenyl) -thiazole or pharmaceutically acceptable acid addition salts of these compounds.
The novel aminothiazoles of this invention are prepared from an appropriately substituted N-aryl thiourea of the
S formula R^NHCNH^, where is as previously defined. The latter compounds are readily prepared from known and readily available amines of the formula For example, when the group
R^ is -(CH2)n-X, unsubstituted or appropriately substituted phenethylamines are employed. Corresponding thenyl or furyl alkylamines will be used to prepare compounds where R^ is χ X
-(CH ) -Y. Where R, is -CH , unsubstituted or substituted 2 m 1 \ χ
- 5 dxphenylmethylamines are appropriate starting materials, while when is -CH^-Ci^-NH-X, unsubstituted or substituted π-phenethylenediamines are employed. In the above, X, Y, n and m are as previously defined. The amine starting material is first converted to the hydrochloride or other hydrohalide salt by reaction with hydrogen chloride or other hydrogen halide, generally by bubbling the gas into a solution of the amine in an inert organic solvent, typically an ether such as diethyl ether, at a temperature of about -10°C to about 10°C. The amine hydrohalide salt is then reacted with ammonium thiocyanate or an alkali metal thiocyanate, such as potassium thiocyanate, in an inert organic solvent, generally an aromatic solvent such as bromobenzene, chlorobenzene, xylene and the like, to form the desired N-aralkyl thiourea. The reaction is preferably conducted in an inert atmosphere, for example under nitrogen, at a temperature of about 110°C to about 25O°C, preferably 150°C to 200°C, for example at the reflux temperature in bromobenzene. The reaction will generally be complete in about 30 minutes to about 6 hours depending on the temperature employed, generally in about 1 to 3 hours at 150 to 200°C. In preparing the N-aralkyl thioureas as described above, it is usually found that some bisaralkyl substituted thiourea is formed, but this can be readily separated from the desired monosubstituted product, for example by recrystallization. It has, however, been found that the reaction of substituted or unsubstituted diphenylmethylamine hydrohalides and ammonium thiocyanate yields predominantly the bis-substituted thiourea, although smaller amounts of the monosubstituted compounds can be obtained in this reaction, and after separation can be used as starting material for the novel aminothiazoles. It has, however, also been found that the bis-substituted thioureas can be used as starting material for the formation of the desired diphenylmethylaminothiazoles of this invention, the bis-substituted
8-126
- 6 thiourea decomposing in situ to generate the monosubstituted compound.
The appropriate H-aralkyl thiourea is converted to the desired aminothiazole by reaction with an appropriately substituted α-haloketone or aldehyde of the formula
R2COCH(Z)R3, wherein R2 and R3 are as previously defined and Z is halo, preferably chloro or bromo. For example, when R2 is phenyl and R3 is hydrogen, α-bromoacetophenone may be employed, while when R2 and R3 are both phenyl an appropriate reagent is a desyl halide, for example 2-chloro-2-phenylacetophenone. Other appropriate α-halo ketones or aldehydes will be readily selected in order to give the desired R^ and R3 substituents in the thiazole ring. The reaction is conducted in an inert organic solvent, typically an n-alkanol of 1 to 6 carbon atoms, preferably in absolute ethanol. Reaction temperatures between about 50° and 175°C are employed, preferably the reflux temperature of the solvent. The reaction is preferably conducted in an inert atmosphere, for example, under nitrogen or another inert gas. The reaction is generally essentially complete in about 1 to 15 hours depending on the temperature employed, for example in about 1 to 4 hours when using ethanol at reflux temperature. The desired compound will be obtained as the hydrohalide salt and the free base can then be prepared from the salt by conventional means, for example by contacting with an excess of a base such as an alkali metal hydroxide or carbonate, followed by extraction of the desired free base aminothiazole with a suitable organic solvent, for example an ether like diethyl ether.
The pharmaceutically acceptable acid addition salts of the novel aminothiazoles are also embraced by the present invention and are readily prepared by contacting the free base with the appropriate mineral or organic acid in either aqueous
4 2 6
- 7 solution or in a suitable organic solvent. The solid salt may then be obtained by precipitation or by evaporation of the solvent. The pharmaceutically acceptable acid addition salts of this invention include, but are not limited to, the hydrochloride, hydrobromide, hydriodide, sulfate, bisulfate, nitrate, phosphate, acetate, lactate, maleate, fumarate, oxalate, citrate, tartrate, succinate, gluconate, methanesulfonate, and the like.
The novel aminothiazoles of this Invention and their pharmaceutically acceptable acid addition salts are useful as anti-inflammatory agents and as regulants of the immune response in warm-blooded animals. The combination of antiinflammatory activity and immune regulant activity is particularly valuable in the treatment of conditions such as rheumatoid arthritis and other diseases associated with immune deficiency and accompanied by inflammation. Thus, the compounds Of the present invention act to relieve the pain and swelling associated with such conditions while also regulating the immune response of the subject and thereby alleviating the underlying immune disorder by maintaining immune competence. The compounds of the present invention may be administered to the subject in need of treatment by conventional routes, such as orally or parenterally, dosages in the range of about 0.10 to about 50 mg/kg body weight of the subject per day, preferably about 0.15 to about 15 mg/kg body weight per day being suitable. However, the optimum dosage for the individual subject being treated will be determined by the person responsible for treatment, generally smaller doses being administered initially and thereafter gradual increments made to determine the most suitable dosage. This will vary according to the particular compound employed and with the subject being treated.
- 8 The compounds may be used in pharmaceutical preparations containing the compound or a pharmaceutically acceptable acid addition salt thereof in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceuti5 cally acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The active compound will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described above. Thus, for oral administration the compounds may be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like. The pharmaceutical compositions may, if desired, contain additional components such as flavorants, sweeteners, excipients and the like. For parenteral administration the compounds may be combined with sterile aqueous or organic media to form injectable solutions or suspensions. For example, solutions of the aminothiazoles in sesame or peanut oil, aqueous propylene glycol and the like may be used, as well as aqueous solutions of water-soluble pharmaceutically acceptable acid addition salts of the compounds. The injectable solutions prepared in this manner may then be administered intravenously, interperitoneally, subcutaneously or intramuscularly, with intravenous and interperitoneal administration being preferred. For local treat25 ment of inflammation the compounds may also be administered topically in the form of ointments, creams, pastes and the like in accord with conventional pharmaceutical practice.
The activity of the compounds of the present invention as anti-inflammatory agents may be determined by pharmacolo30 gical tests, for example the standard carrageenin-induced rat foot edema test using the general procedure described by C. A. Winter et. al., see Proceedings of the Society of Experimental Biology in Medicine, Volume 111, page 544 (1962). In this
- 9 484 36 test, anti-inflarrmatory activity is determined as the percent inhibition of edema formation in the hind paw of male albino rats (generally weighing about 150 to 190 grams) in response to a sub-plantar injection of carrageenin. The earrageenin is injected as a 1% aqueous suspension 1 hour after oral administration of the drug, which is normally given in the form of an aqueous solution or suspension. Edema formation is then assessed 3 hours after the carrageenin injection by comparing the initial volume of the injected paw and the volume after a 3 hour period. The increase in volume 3 hours after carrageenin injection constitutes the individual response. Compounds are considered active if the response between the drug-treated animals (6 rats per group) and the control group, i.e. the animals receiving the vehicle alone, is found to be significant on comparison with the results afforded by standard compounds like acetylsalicyclic acid at 100 mg/kg or phenylbutazone at 33 mg/kg, both by the oral route of administration.
The immune regulant activity of the compounds of the present invention may be determined by such pharmacological tests as the stimulation in vitro of lymphocyte proliferation of murine thymus cells cultured in the presence of Concanavalin A (Con A), employing the general evaluation procedure of V. J. Merluzzi et. al., see Journal of Clinical and Experimental Immunology, Volume 22, page 486 (1975). In this study, four different levels of lymphocyte stimulation assay (LSA) activity were established for the compounds undergoing evaluation, viz., those equal to Con A alone; those superior to Con A activity but less than levamisole, the standard compound of choice in this area; those having an activity equal to levamisole; and those having an activity greater than levamisole. Compounds are considered to be active for the present purposes if they are superior to Concanavalin A.
8 12 6
- 10 The present invention is illustrated by the following examples. However, it should be understood that the invention is not limited to the specific details of these examples.
Example 1
A. Phenethylamine (479 grams, 3.96 moles, Eastman Scintillation Grade) was dissolved in 3500 ml of diethyl ether and the solution was cooled to 0°C. Dry hydrogen chloride gas was bubbled through the stirred solution for 10 minutes and the resulting solids were filtered. The filtrate was then cooled and hydrogen chloride was bubbled through the solution for 10 minutes and the solids collected. This procedure was repeated until acidification of the filtrate with dry hydrogen chloride failed to yield any precipitate. The combined solids were dried in air and then over phosphorous pentoxide under vacuum to provide 514 grams (82%) of phenethylamine hydrochloride, m.p. 216-218°C.
Phenethylamine hydrochloride (257 grains, 1.63 moles) and ammonium thiocyanate (123.6 grams, 1.63 moles) were heated to 160°C in 340 ml bromobenzene under nitrogen. After heating for 90 minutes, the mixture was cooled to room temperature and then to 5°C. This procedure was repeated with a further batch of 257 grams of phenethylamine hydrochloride. The combined solids obtained in the above reaction were stirred in 1.5 1 water and filtered. Recrystallization from isopropyl alcohol yielded 261.5 grams (45%) N-phenethyl thiourea, m.p. 132-134°.
B. N-phenethyl thiourea (225 grains, 1.25 moles) and a-bromoacetophenone (250 grains, 1.25 moles, Aldrich Chem. Co.) in 1500 ml absolute ethanol were heated to reflux temperature for 2 1/2 hours under nitrogen. After reducing the solvent volume by 10%, the reaction mixture was cooled to room temperature and then to 0°C in an ice bath. The solids were filtered off, redissolved in 2,500 ml of absolute ethanol and heated to reflux. The solvent volume was reduced to 2000 ml and the
- 11 reaction mixture cooled to 0°C. This procedure was repeated and after the second recrystallization the solids were collected and dried under vacuum over phosphorous pentoxide, yielding 365 grams (81%) of 2-phenethylamino-4-phenylthiazole hydrobromide, m.p. 169-172°C.
Analysis: Calcd for C17H16N2S.HBr: C, 56.50; H, 4.74; N, 7.68 Found: C, 57.36; H, 5.04; N, 7.83.
Example 2
N-phenethyl thiourea (140 grams, 0.779 moles) and desyl bromide (225 grains, 0.82 moles, Eastman Chem. Co) in 833 ml absolute ethanol were heated at reflux temperature for 2 hours under nitrogen a further 300 ml of absolute ethanol being added during the reaction. The reaction mixture was cooled to 10°C, the solids filtered, recrystallized from absolute ethanol and dried over phosphorous pentoxide to yield 281.0 grams (83%) of 2-phenethylamino-4,5-diphenyl-thiazole hydrobromide, m.p. 171-174°C.
Analysis: Calcd for C^I^Q^S.HBr: C, 63.14; H, 4.84; N, 6.40 Found: C, 62,62; H, 4.82; N, 6.48.
Example 3
N-phenethyl thiourea (2.0 grams, 0.011 moles) and abromopropiophenone (2.34 grams, 0.011 moles, Aldrich Chem.
Co.) in 10 ml absolute ethanol were heated to reflux temperature for 90 minutes under nitrogen. The ethanol was then removed under vacuum, excess ethyl acetate added and the solids filtered and dried over phosphorous pentoxide. Recrystallization from absolute ethanol yielded 2.86 grams (70%) of 5-methyl-2-phenethylamino-4-phenylthiazole hydrobromide, m.p. 172-175°C.
Analysis: Calcd for C^gH^gNjS.HBr: C, 57.59; H, 5.10; N, 7.46 Found: C, 57.67; H, 5.11; N, 7.39.
8 12 6
- 12 Example 4
Following the procedures of Examples 1 and 2, hydrohalide salts of the following compounds were prepared:
Salt X R2 R3 m.p. C. HBr phenyl p-methoxyphenyl hydrogen 135-139 HCl phenyl p-fluorophenyl hydrogen 163-165 HBr p-br omophe ny1 phenyl hydrogen 171-174 HBr p-br omophe ny1 phenyl methyl 150-151.5 HBr p-methoxyphenyl phenyl hydrogen 169-171 HBr p-methoxyphenyl phenyl methyl 149-150.5 HBr p-me thoxyphe ny1 phenyl phenyl 201-205 HCl p-methoxyphenyl p-fluorophenyl hydrogen 156-158
Example 5
a. 2-thenylamine (30 grains, 0.265 moles, Fairfield
Chemical Co.) was dissolved in 400 ml of diethyl ether and cooled to 0°C in an ice bath. Dry hydrogen chloride gas was bubbled through the solution for 5 minutes. The resulting solids were filtered and dried over phosphorous pentoxide to yield 26.7 grains (61%) of 2-thenylamine hydrochloride, m.p. 186-190°C.
2-thenylamine hydrochloride (13.35 grams, 0.089 moles) and ammonium thiocyanate (7.4 grams, 0.089 moles) in 20 ml broraobenzene were heated to reflux temperature for 90 minutes,
The reaction mixture was cooled and the filtered solids washed three times with water. Recrystallization from chloroform and drying over phosphorous pentoxide yielded 5.0 grams (33%) of N-thenyl thiourea, m.p. 99-101°
- 13 48426
Analysis: Calcd for CgHgN2S2: C, 41.83; H, 4.68; N, 16.26 Found: C, 41.56; H, 4.58; N, 16.07.
B. N-thenyl thiourea (2.0 grams, 0.0116 moles) and a-bromoacetophenone (2.3 grams, 0.0116 moles, Aldrich Chem. Co.) in 15 ml absolute ethanol were heated to reflux temperature for 90 minutes under nitrogen. The reaction mixture was cooled and the ethanol removed under vacuum. On dissolving the residue in hot isopropyl alcohol and diluting with diethyl ether, an oil was formed. The diethyl ether was decanted, the oil dissolved in a small amount of ethanol and cooled. The resulting solids were filtered and dried over phosphorous pentoxide, yielding 3.20 grams (78%) of 2-thenylamino-4-phenyl-thiazole hydrobromide, b.p. 115-118°C.
Analysis: Calcd for C^H^NjSj.HBr: C, 47.58; H, 3.71; N, 7.93 Found: C, 47.75; H, 3.74; N, 7.90.
Example 6
N-thenyl thiourea (0.80 grams, 0.0046 moles) and achloro-p-fluoroacetophenone (0.80 grams, 0,0046 moles,
Aldrich Chem. Co.) in 11 ml absolute ethanol were heated at reflux temperature under nitrogen for 90 minutes. After cooling, the ethanol was removed under vacuum and the solids triturated with ethanol, filtered and vacuum dried over phosphorous pentoxide, yielding 0.848 grams (56%) of 2thenylamino-4(p-fluorophenyl)-thiazole hydrochloride, m.p. 184-187°C.
Analysis: Calcd for C^H ^S^F.HCl: C, 51.45; H, 3.70; N, 8.57 Found: C, 51.41; H, 3.63; N, 8.39.
Example 7
Following the procedures of Examples 5 and 6, hydrohalide salts of the following compounds were prepared:
Salt ^3 m. p. °C HBr p-me thoxypheny1 hydrogen 154-158 HBr phenyl methyl 179.5-181.5 HCl thienyl hydrogen 137-142
Example 8
A. Furfurylamine (25.0 grams, 0.257 moles, Pfaltz + Bauer Co.) was dissolved in 1300 ml diethyl ether and cooled to 0°C in an ice bath. Dry hydrogen chloride gas was bubbled through the solution until no further precipitation occurred. The solids were filtered and dried in vacuum over phosphorous pentoxide to yield 33.46 (97%) of furfurylamine hydrochloride, m.p. 147-149°C.
Furfurylamine hydrochloride (33.46 grains, 0.250 moles) and ammonium thiocyanate (38.14 grains, 0.501 moles) in 71 ml bromobenzene were heated under nitrogen at reflux temperature for 20 minutes and then cooled to room temperature. The reaction mixture was mixed with a solution of 125 ml water and 100 ml ethyl acetate and left at room temperature overnight.
The mixture was then diluted to give 500 ml ethyl acetate and 350 ml water and the aqueous layer separated. The organic layer was washed with water and dried over sodium sulfate. After filtration, the organic layer was evaporated to dryness and bromobenzene removed under vacuum. The resulting solids were ground in a mortar and pestle and the fine particles stirred in diethyl ether to remove residual bromobenzene. The solids were then filtered, washed with diethyl ether and vacuum dried over phosphorous pentoxide, yielding 12.06 grams
- 15 48426 (30%) of N-furfuryl thiourea, m.p. 80-91°C.
Analysis: Calcd for CJB_No0S: C, 46.14? H, 5.16? N, 17.93 ο o 2
Found: C, 46.91; H, 4.90; N, 17.57.
B. N-furfuryl thiourea (0.82 grams, 0.005 moles) and a-bromopropiophenone (1.07 grams, 0.005 moles, Aldrich Chem. Co.) in 11 ml absolute ethanol were heated to reflux temperature under nitrogen for 3 hours. After cooling to room temperature, the solvent was removed under vacuum to give a thick brown oil, which was triturated with five 35 ml portions of refluxing ethyl acetate. The ethyl acetate was reduced in volume to about 25 ml and cooled to room temperature. The precipitated solids were filtered, washed with ethyl acetate and vacuum dried over phosphorous pentoxide, yielding 0.585 grams (33%) of 2-furfurylamino-5-methyl-4-phenyl-thiazole hydrobromide, m.p. 15O-153°C.
Analysis: Calcd for OS’.HBr: C, 51.29; H, 4.30; N, 7.97
Found: C, 51.97; H, 4.47; N, 8.42.
Example 9
Following the procedure of Example 8 hydrohalide salts of the following compounds were prepared:
Salt
hydrogen phenyl
Example 10
A. Diphenylmethylamine (25.0 grams, 0.136 moles, Matheson, Coleman + Bell Co.) was dissolved in 660 ml of diethyl ether
HBr
HBr phenyl phenyl
123-126
192-194
8 4 2 6
- 16 and cooled to 0°C. Dry hydrogen chloride gas was bubbled through the solution for 10 minutes, during which time an additional 300 ml of diethyl ether was added to the mixture. The precipitate was filtered, washed with diethyl ether and vacuum dried over phosphorous pentoxide, to yield 28.3 grams (95%) diphenylmethylamine hydrochloride, m.p. 3O3-31O°C (decomposes).
Dipheny lmethy lamine hydrochloride (28.3 grains, 0.129 moles) and ammonium thiocyanate (9.81 grains, 0.129 moles) in
37 ml bromobenzene were heated at reflux temperature under nitrogen for 3 1/2 hours and then cooled to room temperature. The solids were filtered and triturated twice with 200 ml water. The solids were then dissolved in 850 ml ethanol, filtered and evaporated to a volume of about 350 ml. After cooling, the solids were filtered, washed with ethanol and vacuum dried over phosphorous pentoxide to yield 14.72 grains (56%) of N,N'-bis-(diphenylmethyl) thiourea, m.p. 216-217.5°C
Analysis: Calcd for C^yH^^N^S: 79.37; H, 5.92; N, 6.86
Found: C, 79.84; H, 6.05; N, 6.93.
B. Ν,Ν'-bis-(diphenylmethyl) thiourea (1.21 grains, 0.005 moles) and desyl chloride (1.21 grains, 0.005 moles, Aldrich Chem. Co.) in 11 ml absolute ethanol were heated to reflux temperature under nitrogen for 3 hours. After cooling, the reaction mixture was evaporated to dryness, the resulting oil being mixed with about 40 ml diethyl ether. The solids were filtered, cooled with diethyl ether and vacuum dried over phosphorous pentoxide, yielding 1.01 grams (75%) of 4,5-diphenyl-2-diphenylmethylamino-thiazole hydrochloride, m.p. 195-198°C.
Analysis: Calcd for C„OH„„N_S.HC1: C, 73.91; H, 5.09; N, 6.16 Found: C, 73.12; H, 5.28; N, 6.06.
- 17 Example 11
Following the procedures of Example 10, 4-phenyl-2diphenylmethylamino-thiazole hydrobromide was prepared, m.p. 166-168°C.
Example 12
N-phenylethylenediamine (25 grams, 0.184 moles,
Aldrich Chem. Co.) was dissolved in diethyl ether, cooled to 0°C and dry hydrogen ehloride gas bubbled through the solution until no more precipitation occurred. The filtered solids were dried over phosphorous pentoxide, yielding 31.2 grams (98%) N-phenylethylenediamine hydrochloride.
N-phenylethylenediamine hydrochloride (31.2 grams, 0.149 moles) and ammonium thiocyanate (11.3 grains, 0.149 moles) in 31 ml bromobenzene were heated to reflux temperature under nitrogen for 2 hours. After cooling, the resulting solids were filtered off and the bromobenzene was removed from the filtrate under vacuum. The resulting solids were stirred in 250 ml of water, filtered and dissolved in hot isopropyl alcohol. After cooling, the solids were filtered and dried over phosphorous pentoxide, yielding 2.8 grams (8%) of N~(2'-anilinoethyl)thiourea, m.p. 137-140°C.
Analysis: Calcd for COH,XS: C, 55.35; H, 6.71,· N, 21.52.
J-«J «J
Found: C, 55.64; H, 6.75; N, 21.03.
Β. N-(2'-anilinoethyl)-thiourea (0.90 grams, 0.0046 moles) and α-bromoacetophenone (0.92 grams, 0.0046 moles, Aldrich Chem, Co.) in 6 ml absolute ethanol were heated to reflux under nitrogen for 2 hours. After cooling the reaction mixture, the solvent was removed under vacuum. The resulting oil was dissolved in hot isopropyl alcohol, filtered and cooled. The solids were filtered and dried over phosphorous pentoxide, yielding 1.25 grams (73.5%) 2-(2‘-anilinoethylamino)-4-pheny1-thiazole, m.p. 161-165°C.
8 12 6
- 18 Analysis: Calcd for C^^H^^N^S.HBr: C, 54.24; H, 4.82; N, 11.16 Found: C, 54.51; H, 4.59; N, 11.02.
Example 13
Following the procedures of Example 12, hydrohalide 5 salts of the following compounds were prepared:
Salt
HCI
HBr phenyl phenyl 139-143 phenyl methyl 133-136
The immune regulant activity of the aminothiazoles described in Examples 1 to 13 was evaluated by determining their ability to stimulate, in vitro the lymphocyte proliferation of murine thymus cells cultured in the presence of Concanavalin A (Con A) by employing the procedure of V. J.
Merluzzi et. al., as essentially described in the Journal of Clinical and Experimental Immunology. Vol. 22, p. 486 (1975). The cells were derived from male C57B1/6 mice of from 6-8 weeks age, purchased from the Jackson Laboratories of Bar Harbor, Maine and the Con A was obtained from Sigma Chemicals of St. Louis, Missouri. Each cell culture (consisting of 0.10 ml thymus cells stock solution 0.05 ml of Con A stock solution and 0.05 ml of drug solution) was performed in quadruplicate and cellular proliferation was measured, after 48 hours of incubation at 37°C., by pulsing each culture with ®H-thymidine (0.01 ml of specific activity 1.9 C/mM, obtained from Schwarz-Mann, Inc. of Orangeburg, N.Y.) and then deter3 mining the incorporation of H-thymidine into cellular desoxyribonucleic acid (DNA) by an assessment of radioactivity
- 19 using a liquid scintillation counter. The results obtained in this manner are expressed quantitatively in terms of the 3 average counts per minute (cpm) of H-thymidine incorporated at the drug level with maximum activity by the quadruplicate cell cultures. These quadruplicate determinations are employed at eight different concentrations of drugs in the range 0.02 to 50 hg/ml. The highest cpm value obtained is employed in the scoring system. On this basis, four different levels of activity were established in the present lymphocyte stimulation assay (LSA) and these are defined in the manner hereinafter indicated, viz., those levels equal to Con A alone (6,000 + 300 cpm) were assigned a negative value or score of zero; those superior (10,000 + 700 cpm) to Con A activity but less than levamisole were scored as +? while those equal to levami (22,000 + 900 cpm) were scored as ++ and those having an activity (27,000 + 1,000 cpm) greater than levamisole were scored as +++. The LSA activity for the compounds described in the above Examples was +++ in each case.
The anti-inflammatory activity of aminothiazoles of this invention was determined using the standard carrageenininduced rat foot edema test, according to the procedure essentially as described by C. A. Winter et. al., and reported in the Proceedings of the Society for Experimental Biology and Medicine, Vol. Ill, p. 544 (1962). The compounds were administered orally in the form of their previously reported hydrohalide salts at a dose level of 33 mg/kg. The results obtained in this manner are presented in the table below in terms of the percent inhibition of edema formation afforded by each test compound as compared to the non-drug treated control (i.e., aqueous solution with no compound):
8-126
HZ 2-thenyl 4-fluorophenyl hydrogen HBr 2-phen- ethyl phenyl hydrogen HBr 2-phenethyl phenyl phenyl HBr 4-methoxy- - 4-fluorophenyl hydrogen HBr
phenethyl % Inhibition of edema (33 mg/kg, p)
Claims (43)
1. CLAIMS :1. A compound of the formula and the pharmaceutically acceptable acid addition salts z x thereof, wherein R. is: -CH , -(CH) -X, -CH -CH -NH-X or 1 2 n 22 -(CH„) Y, wherein X is phenyl optionally monosubstituted with 2 m alkyl of 1 to 3 carbon atoms, hydroxy, alkoxy of 1 to 3 carbon atoms, chloro, bromo, or fluoro; Y is thienyl or furyl each being optionally monosubstituted with alkyl of 1 to 3 carbon atoms, chloro, bromo or fluoro; n is 2; m is 1 or 2; R^ is phenyl, thienyl or monosubstituted phenyl, said substituent being alkyl of 1 to 3 carbon atoms, hydroxy, alkoxy of 1 to 3 carbon atoms, chloro, bromo or fluoro; and R^ is hydrogen, alkyl of 1 to 3 carbon atoms, phenyl or monosubstituted phenyl, said substituent being alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, chloro, bromo, or fluoro.
2. A compound of Claim 1 wherein R 2 is phenyl.
3. A compound of Claim 2 wherein R 3 is hydrogen.
4. A compound of Claim 2 wherein R 3 is phenyl.
5. A compound of Claim I wherein R^ is -(CH,J -X. 2 Ώ
6. A compound of Claim 5 wherein X is p-methoxyphenyl
7. A compound of Claim 5 wherein X is phenyl.
8. A compound of Claim 7 wherein R 2 is phenyl.
9. A compound of Claim 8 wherein R 3 is hydrogen.
10. A compound of Claim 8 wherein R 3 is phenyl.
11. A compound of Claim 8 wherein R 3 is methyl.
12. A compound of Claim 6 wherein R 2 is p-fluorophenyl and R^ is hydrogen.
13.
14. A compound of Claim 1 wherein R, is -(CH_) -Y. 12m A compound of Claim 13 wherein Y is thienyl.
15. A compound of Claim 14 wherein ra is 1.
16. A compound of Claim 15 wherein R2 is phenyl.
17. A compound of Claim 15 wherein R 2 is p-fluorophenyl.
18. A compound of Claim 16 wherein R^ is hydrogen.
19. A compound of Claim 17 wherein R 3 is hydrogen.
20. A compound of Claim 13 wherein Y is furyl.
21. A compound of Claim 20 wherein m is 1 and R 2 is phenyl.
22. A compound of Claim 21 wherein R 3 is hydrogen.
23. A compound of Claim 21 wherein R 3 is methyl.
24. A compound of Claim 21 wherein R 3 is phenyl.
25. A compound of Claim 1 wherein R, is -CH 1 ' X
26. A compound of Claim 25 wherein X is phenyl.
27. A compound of Claim 26 wherein R 2 is phenyl.
28. A compound of Claim 27 wherein R 3 is hydrogen.
29. A compound of Claim 27 wherein R 3 is phenyl.
30. A compound of Claim 1 wherein R^ is -CH 2 ~CH 2 -NH-X.
31. A compound of Claim 30 wherein X is phenyl.
32. A compound of Claim 31 wherein R 2 is phenyl.
33. A compound of Claim 32 wherein R 3 is hydrogen.
34. A pharmaceutical composition comprising an immune- regulant effective amount of a compound of Claim 1 and a pharmaceutically acceptable carrier.
35. A composition of Claim 34 wherein the compound is 2phenylethylamino-4-phenyl-thiazole.
36. A composition of Claim 34 wherein the compound is 2thenylamino-4-(p-fluorophenyl)-thiazole.
37. A composition of Claim 34 wherein the compound is 2(p-methoxyphenethylamino)-4-(p-fluorophenyl)-thiazole.
38. A compound of the formula (I) as claimed in any one of claims 1 to 33 or a pharmaceutical composition as claimed - 23 in claims 34 to 37 for use in the treatment of rheumatoid arthritis and other diseases associated with immune deficiency and accompanied by inflammation.
39. A process for preparing a compound of formula (I) as defined in claim 1 which comprises reacting a compound of the formula: with a compound of the formula: Z where R^, R 2> and R^ are as defined in claim 1 and Z is chlorine or bromine, and isolating the compound of formula (I) as the hydrochloride or hydrobromide salt and optionally neutralising or converting to another pharmaceutically acceptable· acid addition salt.
40. A process as claimed in claim 39 wherein the compound of formula R 2 CO-CH(Z)-R 3 is 2-chloro-2-phenyl-acetophenone.
41. A process as claimed in claim 39 wherein the compound of formula R 2 CO-CH(Z)-R^ is α-bromoacetophenone.
42. A process as claimed in claim 39 for preparing a compound of the formula (I) wherein R^ is a group X -CH,/ and R 2 , R 3 and X are as defined in claim 1, wherein a bis-substituted thiourea of the formula: II •X CH - NH - C - NH - CH is used in situ as starting material for the compound of the formula: - 24 R -NH-C-NH 2 ·
43. A process as claimed in claim 39 substantially as hereinbefore described with reference to the Examples.
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WO1982001481A1 (en) * | 1980-10-24 | 1982-05-13 | Ronald P Hansen | Dust mitigation system |
JPS57136579A (en) * | 1981-01-21 | 1982-08-23 | Mitsui Toatsu Chem Inc | Thiazolylurea derivative, its preparation, and pharmaceutical composition containing the same |
WO1982002384A1 (en) * | 1981-01-08 | 1982-07-22 | Sakano Isao | Their preparation,and medicinal composition containing same |
JPS57116067A (en) * | 1981-01-12 | 1982-07-19 | Sankyo Kagaku Kk | Novel 8-quinolinesulfonyl derivative, its synthesis and use |
EP0069154B1 (en) * | 1981-01-13 | 1986-10-15 | Mitsui Toatsu Kagaku Kabushiki Kaisha | Novel thiazole compounds, process for their preparation, and medicinal composition containing same |
WO1982002386A1 (en) * | 1981-01-13 | 1982-07-22 | Sakano Isao | Aminothiazole derivatives,process for their preparation,and medicinal composition containing same |
JPS57154175A (en) * | 1981-03-16 | 1982-09-22 | Mitsui Toatsu Chem Inc | 2-thiazoleamine derivative, its preparation, and drug composition comprising it |
DE3227329A1 (en) * | 1982-07-22 | 1984-01-26 | Basf Ag, 6700 Ludwigshafen | METHOD FOR PRODUCING 2-N, N-DISUBSTITUTED AMINOTHIAZOLES |
WO1986003203A1 (en) * | 1984-11-22 | 1986-06-05 | Yoshitomi Pharmaceutical Industries, Ltd. | Thienylthiazole derivatives |
FR2581063B1 (en) * | 1985-04-30 | 1987-07-17 | Chauvin Blache Lab | AMINO-2 THIAZOLES N-SUBSTITUTED, THEIR PREPARATION PROCESS AND THEIR APPLICATION IN THERAPEUTICS |
JPS63152368A (en) * | 1986-06-03 | 1988-06-24 | Sumitomo Pharmaceut Co Ltd | Novel aminoazole derivative and acid addition salt thereof |
JPH075579B2 (en) * | 1986-09-01 | 1995-01-25 | 吉富製薬株式会社 | Aminothiazole compound |
JPH0753666B2 (en) * | 1987-09-14 | 1995-06-07 | 久光製薬株式会社 | Anti-inflammatory agent consisting of substituted diphenylthiazole derivative |
EP0486543B1 (en) * | 1989-08-10 | 1997-10-22 | Commonwealth Scientific And Industrial Research Organisation | Method for producing an electrosuspension of micronised particles |
ATE194338T1 (en) * | 1991-03-07 | 2000-07-15 | Hisamitsu Pharmaceutical Co | DIPHENYLTHIAZOLE DERIVATIVES WITH ANTI-INFLAMMATORY ACTIVITY |
FR2692893B1 (en) * | 1992-06-24 | 1994-09-02 | Sanofi Elf | Branched alkylamino thiazole derivatives, processes for their preparation and pharmaceutical compositions containing them. |
CA2195847A1 (en) * | 1994-07-27 | 1996-02-08 | John J. Talley | Substituted thiazoles for the treatment of inflammation |
FR2754258B1 (en) | 1996-10-08 | 1998-12-31 | Sanofi Sa | AMINOTHIAZOLE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
ES2317889T3 (en) | 2000-03-01 | 2009-05-01 | Janssen Pharmaceutica Nv | DERIVATIVES OF TIAZOLIL 2,4-DISPOSED. |
EP1423113A4 (en) * | 2001-08-13 | 2007-04-18 | Phenex Pharmaceuticals Ag | Nr1h4 nuclear receptor binding compounds |
WO2003027094A2 (en) * | 2001-09-26 | 2003-04-03 | Bayer Pharmaceuticals Corporation | Substituted 3-pyridyl indoles and indazoles as c17,20 lyase inhibitors |
KR100836547B1 (en) | 2002-01-11 | 2008-06-10 | 상꾜 가부시키가이샤 | Amino alcohol derivative or phosphonic acid derivative and medicinal composition containing these |
EP1555264A1 (en) * | 2004-01-15 | 2005-07-20 | Sireen AG | Five-membered heterocyclic compounds as inhibitors of SRC family protein kinase. |
WO2005079788A1 (en) | 2004-02-24 | 2005-09-01 | Sankyo Company, Limited | Amino alcohol compound |
US8088806B2 (en) * | 2005-05-09 | 2012-01-03 | Achillion Pharmaceuticals, Inc. | Thiazole compounds and methods of use |
KR20080091369A (en) | 2006-01-18 | 2008-10-10 | 암젠 인크 | Thiazole compounds as protein kinase b (pkb) inhibitors |
AU2008276521B2 (en) | 2007-07-17 | 2011-11-03 | Amgen Inc. | Heterocyclic modulators of PKB |
CA2693473A1 (en) | 2007-07-17 | 2009-01-22 | Amgen Inc. | Thiadiazole modulators of pkb |
US20130143927A1 (en) * | 2011-06-10 | 2013-06-06 | Calcimedica, Inc. | Compounds that modulate intracellular calcium |
WO2012170931A2 (en) | 2011-06-10 | 2012-12-13 | Calcimedica, Inc. | Compounds that modulate intracellular calcium |
US9856240B2 (en) | 2011-10-19 | 2018-01-02 | Calcimedica, Inc. | Compounds that modulate intracellular calcium |
CN110590785B (en) * | 2019-09-23 | 2021-02-02 | 武汉大学 | Aminothiazole compound, preparation method thereof and application of aminothiazole compound in resisting enterovirus 71 |
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