CA2168231A1 - (thio)carbimidinic acid derivatives and pharmaceutical agents containing them - Google Patents
(thio)carbimidinic acid derivatives and pharmaceutical agents containing themInfo
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- CA2168231A1 CA2168231A1 CA002168231A CA2168231A CA2168231A1 CA 2168231 A1 CA2168231 A1 CA 2168231A1 CA 002168231 A CA002168231 A CA 002168231A CA 2168231 A CA2168231 A CA 2168231A CA 2168231 A1 CA2168231 A1 CA 2168231A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/46—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylureas
- C07C275/58—Y being a hetero atom
- C07C275/60—Y being an oxygen atom, e.g. allophanic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/26—Cyanate or isocyanate esters; Thiocyanate or isothiocyanate esters
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- 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
- A61K31/415—1,2-Diazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
- C07C279/24—Y being a hetero atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C335/04—Derivatives of thiourea
- C07C335/24—Derivatives of thiourea containing any of the groups, X being a hetero atom, Y being any atom
- C07C335/28—Y being a hetero atom, e.g. thiobiuret
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention concerns new pharmaceutical agents containing (thio)carbimidinic acid derivatives of formula I. In addition the invention concerns new (thio)carbimidinic acid derivatives, processes for the production thereof and pharmaceutical agents containing these compounds. The invention concerns pharmaceutical agents containing at least one (thio)carbimidinic acid derivative of formula I as the active substance <IMG> (I), in which R denotes an aliphatic residue or an optionally substituted phenyl group or a carbocyclic group with 7-15 C atoms or a heterocyclic ring system in which the carbocycles and heterocyles can be partially or completely hydrogenated, R1 can be phenyl, phenyl C1-C6-alkyl, hetaryl or hetaryl-C1-C6-alkyl, wherein these residues can be optionally substituted once or several times, R2 denotes hydrogen, C1-C6 alkyl, C1-C6 alkoxy, cyano, amino or hydroxy X denotes oxygen, sulphur or NR2 and Y denotes oxygen or sulphur as well as tautomers, enantiomers and diastereomers and physiologically tolerated salts thereof.
Description
Z168~31 Boehringer M~nnheim GmbH
(Thio)carbimidinic acid derivativeQ and pharmaceutical agents conta; n ; ng these The present invention concerns new pharmaceutical agents which contain (thio)carbimidinic acid derivatives of formula I. In addition the invention relates to new (thio)carbimidinic acid derivatives, processes for their production and their use as antiviral agents.
The invention concerns pharmaceutical agents containing at least one (thio)carbimidinic acid derivative of formula I as the active substance R1-NH-~-NH c y R (I) in which R denotes a straight-chained or branched, saturated or unsaturated aliphatic residue with 1-9 carbon atoms, C3-C8 cycloalkyl, C1-C6 alkoxyalkyl, C1-C6 alkylmercapto-Cl-C6-alkyl, amino-Cl-C6-alkyl, Cl-C6 , 216~231 alkylamino-Cl-C6-alkyl, Cl-C6 dialkylamino-Cl-C6-alkyl, carboxy-Cl-C6-alkyl, C3-C8 cycloalkyl-C1-C6-alkyl; substituted phenyl-C1-C6-alkyl; substituted pyridyl-C1-C6-alkyl;
phenyl which can be optionally substituted once or several times by C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylmercapto, C1-C6 alkylsulfinyl, C1-C6 alkyl-sulfonyl, C2-C6 alkenyl, C2-C6 alkinyl, C2-C6 alkenyloxy, C2-C6 alkenylmercapto, C2-C6 alkinyloxy, C2-C6 alkinylmercapto, amino, C1-C6 alkylamino, di-C1-C6 alkylamino, C1-C6 alkylcarbonylamino, C1-C6 alkylaminocarbonyl, C1-C6 alkoxycarbonyl, hydroxy, benzyloxy, phenylmercapto, phenyloxy, nitro, cyano, halogen, trifluoromethyl, azido, formylamino, carboxy or phenyl;
can represent a carbocyclic monocyclic, bicyclic or tricyclic residue with 7-15 C atoms or a heterocyclic monocyclic, bicyclic or tricyclic ring system in which the unsaturated or aromatic carbocycles and heterocycles can be partially or completely hydrogenated, R1 can be phenyl, phenyl-C1-C6-alkyl, hetaryl or hetaryl-C1-C6 alkyl, wherein the heteroatoms can be the same or different and denote oxygen, sulphur or nitrogen which can be optionally substituted once or several times by a straight-chained or branched, saturated or unsaturated C1-C6 or C2-C6 alkyl residue, C1-C6 alkoxy, C1-C6 alkylmercapto, Cl-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 alkyl-amino, C1-C6 dialkylamino, C1-C6 alkoxycarbonyl, carboxy, carboxy-C1-C6 alkylcarbonyl, carboxy-C2-C6-21G~23 l alkenylcarbonyl, amino, halogen, hydroxy, nitro,cyano, azido, phenyl or benzyloxy, R2 denotes hydrogen, C1-C6 alkyl, C1-C6 alkoxy, cyano, amino or hydroxy X denotes oxygen, sulphur or NR2 and Y denotes oxygen or sulphur as well as tautomers, enantiomers and diastereomers thereof and their physiologically tolerated salts, provided that R1 does not represent a 2,6 methyl-substituted phenyl ring when X = O, Y = S, R = methyl and R2 = H.
Substances of formula I in which R denotes C1-C4 alkyl, allyl, benzyl, 4-bromophenylmethyl or phenyl and R1 represents an unsubstituted or substituted phenyl ring are already known from the literature. In this connection these substances were mainly used as intermediates for the production of heterocyclic end products.
The oxidative cyclization of some substances of formula I is described in Synthesis 1020, 1990. The production of triazines from the said compounds is mentioned in DE
3,516,631; US 4,460,585; US 3,914,224; and Chem. Ber.
105, 3168, 1972. The production of amidinoureas from the amended page 21~8231 - 3a -aforementioned substances is described in IN 152552, (1984) and the production of thiatriazines is described in J. Het. Chem. 21, 1553, 1984. A stimulation of rice growth is ascribed to some compounds of formula I in. J.
Plant. Growth Regul. 2, 123, 1983. Several literature references mention these compounds for the production of the thiadiazoles, dithiazolidines and thiadiazolidines amended page 2l~823l (Indian J. Chem., Sect. B, 15B, 192, 1972; Ind. J. Chem.
12, 134, 1974; J. Chem. Soc. 4191, 1962; J. Indian Chem.
Soc. 38, 988, 1961; J. Chem. Soc. 1064, 1959; J. Chem.
Soc. 379, 1958 and Chem. & Ind. 1482, 1956). The production of some compounds of formula I is described in Zh. Vses, Khim. Obshchest. 19, 109, 1974, Belg.
667875, 1966 and J. Indian Chem. Soc. 38, 979, 1961. The substances are cited in J. Het. Chem. 10, 631, 1973 and J. Chem. Soc. C. 2471, 1967 for the production of triazolol[l,5-alpha]pyrimidines and triazoles. The general action as a herbicide is finally claimed in the application US 2,780,535. However, a pharmacological action of these compounds was not previously known.
Amidinourea derivatives which act antivirally are known from JP-B-43008101 and JP-B-43006612.
The compounds of formula I have valuable pharmacological properties. In particular they have a pronounced antiviral action and are particularly suitable for the treatment of diseases caused by viral or retroviral infections. They are especially suitable for the therapy and prophylaxis of infections caused by DNA viruses such as e.g. the herpes-simplex virus, the cytomegalo-virus, papilloma viruses, the varicella-zoster virus or Epstein-Barr virus or RNA viruses such as Toga viruses or especially retroviruses such as the oncoviruses HTLV
I and II as well as the lentiviruses visna and human immunodeficiency virus HIV-l and 2. Above all the compounds of formula I appear to be particularly suitable for the treatment of the clinical manifestations of the retroviral HIV infection in humans, the advanced stage of the AIDS-related complex amended page - 4a -(ARC) and the complete clinical picture of AIDS.
Viral infections of mammals in particular of humans are widespread. Despite intensive efforts it has hitherto not been possible to provide chemotherapeutics that amended page 21~8231 interfere causally or symptomatically with the viral or retroviral-dependent disease process with a recognizable substantial success. Nowadays it is not possible to heal or to favourably chemotherapeutically influence the symptoms of certain virus diseases such as for example the Acquired Immune Deficiency Syndrome (AIDS), the AIDS-related-complex (ARC) and precursors thereof, herpes, cytomegalo-virus (CMV), influenza and other virus infections. At present 3'-azido-3'-deoxy-thymidine (AZT) known as Zidovudine or Retrovir~ is almost all that is for example available for the treatment of AIDS.
However AZT is characterized by a very narrow therapeutic range and by very severe toxicities which already occur in the therapeutic range (Hirsch, M.S.
(1988), J. Infec. Dis. 157, 427-431). The compounds of the general formula I do not have these disadvantages.
They act antivirally without being cytotoxic in pharmacologically relevant doses.
It has now been possible to prove that compounds of the general formula I inhibit the replication of DNA and RNA
viruses at the level of virus-specific DNA and RNA
transcription. The substances can influence the replication of retroviruses by inhibiting the enzyme-reverse transcriptase (cf. Proc. Natl. Acad. Sci. USA
83, 1911, 1986 and Nature 325, 773, 1987).
The invention also concerns new (thio)carbimidinic acid derivatives of formula I
R1 N C NH C Y (I) 21~8231 in which R denotes a straight-chained or branched, saturated or unsaturated aliphatic residue with 1-9 carbon atoms, C3-C8 cycloalkyl, Cl-C6 alkoxyalkyl, Cl-C6 alkylmercapto-Cl-C6-alkyl, amino-Cl-C6-alkyl, Cl-C6 alkylamino-Cl-C6-alkyl, Cl-C6 dialkylamino-Cl-C6-alkyl, carboxy-Cl-C6-alkyl, C3 - C8 cycloalkyl-Cl-C6-alkyl; substituted phenyl-Cl-C6-alkyl; substituted pyridyl-Cl-C6-alkyl;
phenyl which can be optionally substituted once or several times by Cl-C6 alkyl, Cl-C6 alkoxy, Cl-C6 alkylmercapto, Cl-C6 alkylsulfinyl, Cl-C6 alkyl-sulfonyl, C2-C6 alkenyl, C2-C6 alkinyl, C2-C6 alkenyloxy, C2-C6 alkenylmercapto, C2-C6 alkinyloxy, C2-C6 alkinylmercapto, amino, Cl-C6 alkylamino, di-Cl-C6 alkylamino, Cl-C6 alkylcarbonylamino, Cl-C6 alkylaminocarbonyl, Cl-C6 alkoxycarbonyl, hydroxy, benzyloxy, phenylmercapto, phenyloxy, nitro, cyano, halogen, trifluoromethyl, azido, formylamino, carboxy or phenyl;
can represent a carbocyclic monocyclic, bicyclic or tricyclic residue with 7-15 C atoms or a heterocyclic monocyclic, bicyclic or tricyclic ring system in which the unsaturated or aromatic carbocycles and heterocycles can be partially or completely hydrogenated, Rl can be phenyl, phenyl-Cl-C6-alkyl, hetaryl or hetaryl-Cl-C6-alkyl, wherein the heteroatoms can be the same or different and denote amended page 21~8231 oxygen, sulphur or nitrogen which can be optionally substituted once or several times by a straight-chained or branched, saturated or unsaturated aliphatic residue C1-C6 alkoxy, C1-C6 alkylmercapto, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy-carbonyl, carboxy, carboxy-C1-C6-alkylcarbonyl, carboxy-C2-C6-alkenylcarbonyl, amino, halogen, hydroxy, nitro, cyano, azido, phenyl or benzyloxy, R2 denotes hydrogen, C1-C6 alkyl, C1-C6 alkoxy, cyano, amino or hydroxy X denotes oxygen, sulphur or NR2 and Y denotes oxygen or sulphur as well as tautomers, enantiomers and diastereomers thereof and their physiologically tolerated salts, provided that R does not denote C1-C4 alkyl, allyl, benzyl, 4-bromophenylmethyl or phenyl if R1 represents an unsubstituted or substituted phenyl ring.
An aliphatic residue R in compounds of the general formula I denotes a straight-chained or branched alkyl, alkenyl or alkinyl residue with 1-9, preferably 2-7 carbon atoms such as e.g. a propyl, isopropyl, butyl, isobutyl, pentyl, hexyl or heptyl residue. C2-C7 alkenyl and alkinyl residues come into consideration as unsaturated residues and preferably C2-C5 such as an allyl, dimethylallyl, butenyl, isobutenyl, pentenyl or propinyl residue. Cyclopentyl and cyclohexyl are 21~8231 preferably used as the C3-C8 cycloalkyl residue. In the case of C1-C6 alkoxyalkyl, C1-C6 alkylmercaptoalkyl, aminoalkyl, C1-C6 alkylaminoalkyl, C1-C6-dialkylamino-alkyl and carboxyalkyl, the alkyl residue has 1 - 6 carbon atoms, preferably 1 - 3 carbon atoms. In the case of C3-C8 cycloalkylalkyl, phenyl-C1-C3-alkyl and pyridoxyl-C1-C3-alkyl, cyclopentylmethyl, benzyl, phenethyl, pyridylmethyl and pyridylethyl are preferred.
If R denotes a phenyl ring this can be substituted once, twice or three times. The substituents can independently of one another be in the o, m or p position.
A carbocyclic ring with 7-15 C atoms can be monocyclic, bicyclic or tricyclic and each can have 5 or 6 C atoms per ring. This ring can be saturated, unsaturated, partially saturated or aromatic. The following ring systems are mentioned as examples: the naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, acenaphthylenyl, norbornyl, adamantyl ring or a C3-C7 cycloalkyl or C5-C8 cycloalkenyl group. In addition the carbocyclic ring can be monosubstituted or disubstituted in which the substituents can, independently of each other, be in the o or m position and are selected from the group comprising C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylmercapto, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C2-C6 alkenyl, C2-C6 alkinyl, C3-C6 alkenyloxy, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkylcarbonyl-amino, C1-C6 alkylaminocarbonyl, C1-C6 alkoxycarbonyl, amino, hydroxy, nitro, azido, trifluoromethyl, cyano or halogen.
The heterocyclic monocyclic, bicyclic or tricyclic ring systems of the residue R contain 5 or 6 carbon atoms per ~168231 ring in which 1-4 or 1-5 C atoms can be substituted by the heteroatoms oxygen, sulphur and/or nitrogen. The ring systems can be aromatic, or partially or completely hydrogenated. The following ring systems are mentioned as examples: the pyridine, pyrimidine,-pyridazine, pyrazine, triazine, pyrrole, pyrazole, imidazole, triazole, thiazole, oxazole, isoxazole, oxadiazole, furazan, furan, thiophene, indole, quinoline, isoquinoline, coumarone, thionaphthene, benzoxazole, benzthiazole, indazole, benzimidazole, benztriazole, chromene, phthalazine, quinazoline, quinoxaline, methylenedioxy-benzene, carbazole, acridine, phenoxazine, phenothiazine, phenazine or purine system in which the unsaturated or aromatic carbocycles and heterocycles can be partially or completely hydrogenated. The heterocyclic ring system can in addition be monosubstituted or disubstituted, the substituents being independently of one another preferably in the o or m position.
R preferably denotes unsubstituted phenyl or phenyl which is substituted once or twice by C1-C6 alkyl, Cl-C6 alkoxy, C1-C6 alkylmercapto, Cl-C6 alkylsulfinyl, Cl-C6 alkylsulfonyl, C2-C4 alkenyl, C2-C6 alkinyl, C3-C4 alkenyloxy, Cl-C6 alkylamino, Cl-C6 dialkylamino, Cl-C6 alkylcarbonylamino, Cl-C6 alkylaminocarbonyl, Cl-C6 alkoxycarbonyl, amino, hydroxy, nitro, azido, trifluoromethyl, cyano or halogen. The "alkyl" moieties of the said substituents preferably contain up to three carbon atoms.
Heterocyclic ring systems and the hetaryl residues are preferably pyrrole, imidazole, furan, thiophene, pyridine, pyrimidine, thiazole, triazine, indole, quinoline, isoquinoline, coumarone, thionaphthene, ~168231 benzimidazole, quinazoline, methylenedioxybenzene, ethylenedioxybenzene, carbazole, acridine and phenothiazine wherein the heterocyclic rings can be substituted once or twice by C1-C6 alkyl, Cl-C6 alkoxy, C1-C6 alkylmercapto, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C2-C4 alkenyl, C2-C6 alkinyl, C3-C6 alkenyloxy, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkylcarbonylamino, C1-C6 alkylaminocarbonyl, C1-C6 alkoxycarbonyl, amino, hydroxy, nitro, azido, trifluoromethyl, cyano or halogen. The "alkyl" moieties of the said substituents preferably contain up to three carbon atoms.
If R1 denotes a phenyl ring or an aromatic, heterocyclic ring these can preferably be substituted once or several times by C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkinyl, C1-C3 alkoxy, C1-C3 alkylmercapto, C1-C3 alkylamino, C1-C3 dialkylamino, C1-C3 alkoxycarbonyl, carboxyethyl-carbonyl, carboxyvinylcarbonyl, amino, halogen, hydroxy, cyano and azido and the aromatic heterocyclic ring can have 3-7 carbon atoms wherein up to 4 of these ring atoms can be substituted by the heteroatoms oxygen, sulphur or/and nitrogen. The following heterocycles are mentioned as examples: the furan, oxazole, isoxazole, oxadiazole, triazole, pyridine, pyridazine, pyrimidine or pyrazine ring.
Particularly preferred residues for R are C3-C6 alkyl, C2-C6 alkenyl, C2-C4 alkinyl, benzyl, phenethyl, pyridylmethyl, pyridylethyl which are optionally monosubstituted or disubstituted with C1-C3 alkyl, C1-C3 alkoxy or halogen, phenyl which is monosubstituted or disubstituted by C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylmercapto, allyl, allyloxy, C1-C3 alkylamino, di-C1-C3 alkylamino, amino, hydroxy, azido, trifluoromethyl, ;~168231 cyano or halogen or phenyl which is trisubstituted by methyl or halogen, naphthyl, anthracenyl, indenyl, acenaphthylenyl, phenanthrenyl, adamantyl, cyclohexyl, cyclohexenyl, furyl, thienyl, pyridyl, pyrimidinyl, thiazolyl, indolyl, quinolinyl, benzimidazolyl, methylenedioxy-phenyl, carbazolyl and phenothiazinyl and derivatives of the aforementioned carbocyclic or heterocyclic rings that are monosubstituted or disubstituted by methyl or halogen.
Particularly preferred residues for Rl are phenyl and aromatic rings containing nitrogen with 5-6 ring atoms which are substituted once or several times with hydrogen, methyl, ethyl, isopropyl, allyl, methoxy, ethoxy, methylmercapto, ethylmercapto, methylamino, methoxycarbonyl, ethoxycarbonyl, carboxyvinylcarbonyl, amino, azido, cyano, hydroxy and halogen in which chlorine and bromine are particularly preferred for halogen.
Hydrogen, amino and hydroxy are particularly preferred for R2.
Oxygen and sulphur come into especially preferable consideration for X.
Y preferably denotes sulphur.
The compounds of the general formula I according to the invention are produced according to processes known from the literature by reacting isocyanates or thioisocyanates of the general formula II
21~8231 Rl - N = C = X (II) in which Rl has the meaning stated above and X is oxygen or sulphur with isoureas or isothioureas of the general formula III
R2N=C - Y - R (III) in which R, R2 and Y have the meanings stated above, in a suitable inert solvent at room temperature to reflux temperature optionally in the presence of a base such as triethylamine and if desired compounds of the formula I
are subsequently converted into other compounds of formula I and subsequently purified chromatographically or by recrystallization.
The additional conversion of compounds of formula I into other compounds of formula I relates for example to the production of derivatives of the general formula I in which X represents the residue NR2. These compounds are produced by reacting compounds of the general formula I
in which X=S or S denotes alkyl with amines of formula H2NR2 in a polar solvent optionally under pressure or in the presence of a carbodiimide at temperatures between 0C and the boiling point of the solvent.
The pharmaceutical agents contain at least one compound of formula I for the treatment of viral infections and can be administered enterally or parenterally in a liquid or solid form. In this case the usual forms of administration come into consideration such as for example tablets, capsules, coated tablets, syrups, solutions or suspensions. Water is preferably used as the injection medium which contains the usual additives for injection solutions such as stabilizing agents, solubilizers and buffers. Such additives are for example tartrate and citrate buffer, ethanol, complexing agents such as ethylenediaminetetraacetic acid and non-toxic salts thereof, high-molecular polymers such as liquid polyethylene oxide to regulate viscosity. Liquid carrier substances for injection solutions have to be sterile and are preferably dispensed into ampoules. Solid carriers are for example starch, lactose, mannitol, methylcellulose, talcum, highly dispersed silicic acids, higher molecular fatty acids such as stearic acid, gelatin, agar-agar, calcium phosphate, magnesium stearate, animal or vegetable fats, solid high-molecular polymers such as polyethylene glycols etc.. Preparations which are suitable for oral applications can if desired, contain flavourings and sweeteners.
The dose can depend on various factors such as mode of administration, species, age or individual condition.
The compounds according to the invention are usually administered in amounts of 0.1 - 100 mg, preferably 0.2 - 80 mg per day and per kg body weight. The daily dose is preferably divided into 2 to 5 applications in which 1-2 tablets having a content of active substance of 0.5 - 500 mg are administered at each application.
The tablets can also be retarded by which means the number of applications is reduced to 1-3 times per day.
The content of active substance in retarded tablets can be 2 - 1000 mg. The active substance can also be administered by continuous infusion in which case amounts of 5 - 1000 mg per day are usually adequate. The pharmaceutical agents can also be administered combined with other antiviral agents such as AZT.
~16~231 In addition to the compounds mentioned in the examples and those derived by combining all meanings of substituents stated in the claims, the following compounds of formula I come into consideration within the sense of the present invention which can be present as racemic mixtures or in an optical active form or as pure R and S enantiomers:
1. N-(phenylaminothiocarbonyl)thiocarbimidinic acid-2-(4-methylpentyl)ester 2. N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid 2-(4-methylpentyl) ester 3. N-(3-fluorophenylaminothiocarbonyl)thiocarbimidinic acid 2-(4-methylpentyl) ester 4. N-(4-dimethylaminophenylaminothiocarbonyl)thio-carbimidinic acid 2-(4-methylpentyl) ester 5. N-(4-hydroxycarbonylphenylaminothiocarbonyl)thio-carbimidinic acid 2-(4-methylpentyl) ester 6. N-(4-hydroxysulfonylphenylaminothiocarbonyl)thio-carbimidinic acid 2-(4-methylpentyl) ester 7. N-(4-carboxyvinylcarbonylphenylaminothiocarbonyl)-thio-carbimidinic acid 2-(4-methylpentyl) ester 8. N-(4-methoxyphenylaminothiocarbonyl)thio-carbimidinic acid 2-(4-methylpentyl) ester ~168231 9. N-(3-trifluoromethylphenylaminothiocarbonyl)thio-carbimidinic acid 2-(4-methylpentyl) ester 10. N-(2-bromophenylaminothiocarbonyl)thiocarbimidinic acid 2-(4-methylpentyl) ester 11. N-(4-methylphenylaminothiocarbonyl)thiocarbimidinic acid 2-(4-methylpentyl) ester 12. N-(4-nitrophenylaminothiocarbonyl)thiocarbimidinic acid 2-(4-methylpentyl) ester 13. N-(4-isopropylphenylaminothiocarbonyl)thio-carbimidinic acid 2-(4-methylpentyl) ester 14. N-(3-cyanophenylaminothiocarbonyl)thiocarbimidinic acid 2-(4-methylpentyl) ester 15. N-(4-methylsulfonylphenylaminothiocarbonyl)thio-carbimidinic acid 2-(4-methylpentyl) ester 16. N-(2-pyridylaminothiocarbonyl)thiocarbimidinic acid 2-(4-methylpentyl) ester 17. N-(3-pyridylaminothiocarbonyl)thiocarbimidinic acid 2-(4-methylpentyl) ester 18. N-(4-pyridylaminothiocarbonyl)thiocarbimidinic acid 2-(4-methylpentyl) ester 19. N-[(5-bromo-2-pyridyl)aminothiocarbonyl]-thio-carbimidinic acid 2-(4-methylpentyl) ester ~1~3231 20. N-(2-thienylaminothiocarbonyl)-thiocarbimidinic acid 2-(4-methylpentyl) ester 21. N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid methyl ester 22. N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid ethyl ester 23. N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid benzyl ester 24. N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid (2-chlorobenzyl) ester 25. N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid cyclohexyl ester 26. N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid (4(5)-imidazolylmethyl) ester 27. N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid hexyl ester 28. N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid (2-pyridylethyl) ester 29. N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid (3-chlorobenzyl) ester 30. N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid (4-chlorobenzyl) ester 31. N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid (2-aminoethyl) ester 32. N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid (2,5-dihydroxyphenyl) ester -33. N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid (2-carboxyethyl) ester 34. N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid isopropentyl ester 35. N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid n-butyl ester 36. N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid (2-dimethylaminoethyl) ester 37. N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid (3-dimethylaminopropyl) ester 38. N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid (2-pyridyl) ester 39. N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid (3-methyl-2-pyridyl) ester 40. N-(phenylaminocarbonyl)thiocarbimidinic acid methyl ester 41. N-(phenylaminocarbonyl)thiocarbimidinic acid benzyl ester ~1~3231 42. N-(phenylaminocarbonyl)thiocarbimidinic acid phenyl ester 43. N-(phenylaminocarbonyl)thiocarbimidinic acid 2-(4-methylpentyl) ester 44. N-(phenylaminothiocarbonyl)carbimidinic acid ethyl ester 45. N-(phenylaminothiocarbonyl)carbimidinic acid allyl ester 46. N-(phenylaminothiocarbonyl)carbimidinic acid (3-methylphenyl) ester 47. N-(phenylaminothiocarbonyl)carbimidinic acid 2-(5-methylpyridyl) ester Example N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid 2-~4-methylpentyl)ester a) 22.83 g (0.3 mol) thiourea and 55 g (0.33 mol) 2-bromo-4-methylpentane are heated for 24 hours in 40 ml ethanol under reflux. The solvent was subsequently concentrated by evaporation, the residue was admixed with 250 ml ether and suction filtered.
After recrystallizing from acetone 52 g 2-(4-methyl-pentyl)isothiuronium bromide is obtained with a ~1~8231 melting point of 143C.
b) 2.65 g (11 mmol) 2-(4-methylpentyl)isothiuronium bromide (example la), 1.69 g (10 mmol) 4-chloro-phenylisothiocyanate and 1.12 g (11 mmol) triethylamine were stirred in 20 methylene chloride for 5 hours at 25C. Subsequently the organic phase was washed with 1 N cold hydrochloric acid and hydrogen carbonate solution and concentrated by evaporation. The residue was recrystallized from isopropanol/isohexane (1:3). 2.1 g of the title compound with a melting point of 117-119C was obtained.
Exampl~ 2 The following compounds are obtained analogously to example 1:
a) N-(phenylaminothiocarbonyl)thiocarbimidinic acid 2-(4-methylpentyl) ester with a melting point of 95-96C.
b) N-(3-fluorophenylaminothiocarbonyl)thiocarbimidinic acid 2-(4-methylpentyl) ester with a melting point of 80-95C.
c) N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid methyl ester with a melting point of 145-146C.
d) N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid ethyl ester with a melting point of 125-126C.
i~168231 e) N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid benzyl ester with a melting point of 133-135C.
f) N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid cyclohexyl ester with a melting point of 144-146C.
g) N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid 3-chlorobenzyl ester with a melting point of 123-124C.
h) N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid 4-chlorobenzyl ester with a melting point of 147-149C.
i) N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid hexyl ester with a melting point of 106-107C.
j) N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid butyl ester with a melting point of 126-128C.
k) N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid 2-methylallyl ester with a melting point of 139-141C.
l) N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid 2-(2-pyridyl)ethyl ester with a melting point of 132-134C.
m) N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid 2-(4-morpholino)ethyl ester with a melting point of 121-123C.
~168231 n) N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid phenyl ester with a melting point of 127-129C.
o) N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid (4-methylpyridin-2-yl)-methyl ester with a melting point of 148-149C.
p) N-[(4-chlorophenyl)methylaminothiocarbonyl]thio-carbimidinic acid 2-(4-methylpentyl) ester as an oil.
Rf value: 0.7 (toluene:dioxane:water) q) N-[2-(4-chlorophenyl)ethylaminothiocarbonyl]thio-carbimidinic acid 2-(4-methylpentyl) ester as an oil.
Rf value: 0.25 (toluene) r) N-(4-aminosulfonylphenylaminothiocarbonyl)thio-carbimidinic acid 2-(4-methylpentyl) ester with a melting point of 113-116C.
s) N-(4-carboxyphenylaminothiocarbonyl)thiocarbimidinic acid 2-(4-methylpentyl) ester with a melting point of 187-191C.
t) N-(phenylaminothiocarbonyl)thiocarbimidinic acid 1-(2-methyl)phenethyl ester with a melting point of 84-86C.
Example 3 N-(phenylaminocarbonyl)thiocsrbimidinic acid 2-~4-methylpentyl) ester 2.73 g of the title compound is obtained analogously to example lb as a colourless resin ~TLC, mobile solvent:
toluene:dioxane:water (90:20:0.2), Rf=0.64 from 2.65 g (11 mmol) 2-(4-methylpentyl)isothiuronium bromide, 1.19 g (10 mmol) phenylisocyanate and 1.12 g (11 mmol) triethylamine in 20 ml methylene chloride.
~xample 4 Antiviral efficacy The antiviral efficacy of some selected substances was examined in vivo as well as in vitro (inhibition of reverse transcriptase RT).
a) MT2/MTT test system (in vivo) MT2 cells are infected with HIV-1 (HTLV III B
isolate). After a 7 day incubation a MTT test was carried out which determined the vitality of the cells. The vitality of the cells correlates with the extent of virus production. IC50 values are stated in the following table i.e. that concentration of the substances that causes a 50 % inhibition.
21~8~31 b) Inhibition of RT (in vitro) The extent of the inhibition of RT activity is determined in a non-radioactive microtitre plate test. The amount of nucleotides incorporated into the DNA to be synthesized is determined photometrically.
IC50 values (ug/ml) Example No MT2 RT
1 0.6 0.6 2 b 3.3 1.0 2 e < 3 2.45 2 f < 3 0.103 2 g < 3 0.33 2 j < 3 0.76 2 n - 0.9
(Thio)carbimidinic acid derivativeQ and pharmaceutical agents conta; n ; ng these The present invention concerns new pharmaceutical agents which contain (thio)carbimidinic acid derivatives of formula I. In addition the invention relates to new (thio)carbimidinic acid derivatives, processes for their production and their use as antiviral agents.
The invention concerns pharmaceutical agents containing at least one (thio)carbimidinic acid derivative of formula I as the active substance R1-NH-~-NH c y R (I) in which R denotes a straight-chained or branched, saturated or unsaturated aliphatic residue with 1-9 carbon atoms, C3-C8 cycloalkyl, C1-C6 alkoxyalkyl, C1-C6 alkylmercapto-Cl-C6-alkyl, amino-Cl-C6-alkyl, Cl-C6 , 216~231 alkylamino-Cl-C6-alkyl, Cl-C6 dialkylamino-Cl-C6-alkyl, carboxy-Cl-C6-alkyl, C3-C8 cycloalkyl-C1-C6-alkyl; substituted phenyl-C1-C6-alkyl; substituted pyridyl-C1-C6-alkyl;
phenyl which can be optionally substituted once or several times by C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylmercapto, C1-C6 alkylsulfinyl, C1-C6 alkyl-sulfonyl, C2-C6 alkenyl, C2-C6 alkinyl, C2-C6 alkenyloxy, C2-C6 alkenylmercapto, C2-C6 alkinyloxy, C2-C6 alkinylmercapto, amino, C1-C6 alkylamino, di-C1-C6 alkylamino, C1-C6 alkylcarbonylamino, C1-C6 alkylaminocarbonyl, C1-C6 alkoxycarbonyl, hydroxy, benzyloxy, phenylmercapto, phenyloxy, nitro, cyano, halogen, trifluoromethyl, azido, formylamino, carboxy or phenyl;
can represent a carbocyclic monocyclic, bicyclic or tricyclic residue with 7-15 C atoms or a heterocyclic monocyclic, bicyclic or tricyclic ring system in which the unsaturated or aromatic carbocycles and heterocycles can be partially or completely hydrogenated, R1 can be phenyl, phenyl-C1-C6-alkyl, hetaryl or hetaryl-C1-C6 alkyl, wherein the heteroatoms can be the same or different and denote oxygen, sulphur or nitrogen which can be optionally substituted once or several times by a straight-chained or branched, saturated or unsaturated C1-C6 or C2-C6 alkyl residue, C1-C6 alkoxy, C1-C6 alkylmercapto, Cl-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 alkyl-amino, C1-C6 dialkylamino, C1-C6 alkoxycarbonyl, carboxy, carboxy-C1-C6 alkylcarbonyl, carboxy-C2-C6-21G~23 l alkenylcarbonyl, amino, halogen, hydroxy, nitro,cyano, azido, phenyl or benzyloxy, R2 denotes hydrogen, C1-C6 alkyl, C1-C6 alkoxy, cyano, amino or hydroxy X denotes oxygen, sulphur or NR2 and Y denotes oxygen or sulphur as well as tautomers, enantiomers and diastereomers thereof and their physiologically tolerated salts, provided that R1 does not represent a 2,6 methyl-substituted phenyl ring when X = O, Y = S, R = methyl and R2 = H.
Substances of formula I in which R denotes C1-C4 alkyl, allyl, benzyl, 4-bromophenylmethyl or phenyl and R1 represents an unsubstituted or substituted phenyl ring are already known from the literature. In this connection these substances were mainly used as intermediates for the production of heterocyclic end products.
The oxidative cyclization of some substances of formula I is described in Synthesis 1020, 1990. The production of triazines from the said compounds is mentioned in DE
3,516,631; US 4,460,585; US 3,914,224; and Chem. Ber.
105, 3168, 1972. The production of amidinoureas from the amended page 21~8231 - 3a -aforementioned substances is described in IN 152552, (1984) and the production of thiatriazines is described in J. Het. Chem. 21, 1553, 1984. A stimulation of rice growth is ascribed to some compounds of formula I in. J.
Plant. Growth Regul. 2, 123, 1983. Several literature references mention these compounds for the production of the thiadiazoles, dithiazolidines and thiadiazolidines amended page 2l~823l (Indian J. Chem., Sect. B, 15B, 192, 1972; Ind. J. Chem.
12, 134, 1974; J. Chem. Soc. 4191, 1962; J. Indian Chem.
Soc. 38, 988, 1961; J. Chem. Soc. 1064, 1959; J. Chem.
Soc. 379, 1958 and Chem. & Ind. 1482, 1956). The production of some compounds of formula I is described in Zh. Vses, Khim. Obshchest. 19, 109, 1974, Belg.
667875, 1966 and J. Indian Chem. Soc. 38, 979, 1961. The substances are cited in J. Het. Chem. 10, 631, 1973 and J. Chem. Soc. C. 2471, 1967 for the production of triazolol[l,5-alpha]pyrimidines and triazoles. The general action as a herbicide is finally claimed in the application US 2,780,535. However, a pharmacological action of these compounds was not previously known.
Amidinourea derivatives which act antivirally are known from JP-B-43008101 and JP-B-43006612.
The compounds of formula I have valuable pharmacological properties. In particular they have a pronounced antiviral action and are particularly suitable for the treatment of diseases caused by viral or retroviral infections. They are especially suitable for the therapy and prophylaxis of infections caused by DNA viruses such as e.g. the herpes-simplex virus, the cytomegalo-virus, papilloma viruses, the varicella-zoster virus or Epstein-Barr virus or RNA viruses such as Toga viruses or especially retroviruses such as the oncoviruses HTLV
I and II as well as the lentiviruses visna and human immunodeficiency virus HIV-l and 2. Above all the compounds of formula I appear to be particularly suitable for the treatment of the clinical manifestations of the retroviral HIV infection in humans, the advanced stage of the AIDS-related complex amended page - 4a -(ARC) and the complete clinical picture of AIDS.
Viral infections of mammals in particular of humans are widespread. Despite intensive efforts it has hitherto not been possible to provide chemotherapeutics that amended page 21~8231 interfere causally or symptomatically with the viral or retroviral-dependent disease process with a recognizable substantial success. Nowadays it is not possible to heal or to favourably chemotherapeutically influence the symptoms of certain virus diseases such as for example the Acquired Immune Deficiency Syndrome (AIDS), the AIDS-related-complex (ARC) and precursors thereof, herpes, cytomegalo-virus (CMV), influenza and other virus infections. At present 3'-azido-3'-deoxy-thymidine (AZT) known as Zidovudine or Retrovir~ is almost all that is for example available for the treatment of AIDS.
However AZT is characterized by a very narrow therapeutic range and by very severe toxicities which already occur in the therapeutic range (Hirsch, M.S.
(1988), J. Infec. Dis. 157, 427-431). The compounds of the general formula I do not have these disadvantages.
They act antivirally without being cytotoxic in pharmacologically relevant doses.
It has now been possible to prove that compounds of the general formula I inhibit the replication of DNA and RNA
viruses at the level of virus-specific DNA and RNA
transcription. The substances can influence the replication of retroviruses by inhibiting the enzyme-reverse transcriptase (cf. Proc. Natl. Acad. Sci. USA
83, 1911, 1986 and Nature 325, 773, 1987).
The invention also concerns new (thio)carbimidinic acid derivatives of formula I
R1 N C NH C Y (I) 21~8231 in which R denotes a straight-chained or branched, saturated or unsaturated aliphatic residue with 1-9 carbon atoms, C3-C8 cycloalkyl, Cl-C6 alkoxyalkyl, Cl-C6 alkylmercapto-Cl-C6-alkyl, amino-Cl-C6-alkyl, Cl-C6 alkylamino-Cl-C6-alkyl, Cl-C6 dialkylamino-Cl-C6-alkyl, carboxy-Cl-C6-alkyl, C3 - C8 cycloalkyl-Cl-C6-alkyl; substituted phenyl-Cl-C6-alkyl; substituted pyridyl-Cl-C6-alkyl;
phenyl which can be optionally substituted once or several times by Cl-C6 alkyl, Cl-C6 alkoxy, Cl-C6 alkylmercapto, Cl-C6 alkylsulfinyl, Cl-C6 alkyl-sulfonyl, C2-C6 alkenyl, C2-C6 alkinyl, C2-C6 alkenyloxy, C2-C6 alkenylmercapto, C2-C6 alkinyloxy, C2-C6 alkinylmercapto, amino, Cl-C6 alkylamino, di-Cl-C6 alkylamino, Cl-C6 alkylcarbonylamino, Cl-C6 alkylaminocarbonyl, Cl-C6 alkoxycarbonyl, hydroxy, benzyloxy, phenylmercapto, phenyloxy, nitro, cyano, halogen, trifluoromethyl, azido, formylamino, carboxy or phenyl;
can represent a carbocyclic monocyclic, bicyclic or tricyclic residue with 7-15 C atoms or a heterocyclic monocyclic, bicyclic or tricyclic ring system in which the unsaturated or aromatic carbocycles and heterocycles can be partially or completely hydrogenated, Rl can be phenyl, phenyl-Cl-C6-alkyl, hetaryl or hetaryl-Cl-C6-alkyl, wherein the heteroatoms can be the same or different and denote amended page 21~8231 oxygen, sulphur or nitrogen which can be optionally substituted once or several times by a straight-chained or branched, saturated or unsaturated aliphatic residue C1-C6 alkoxy, C1-C6 alkylmercapto, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkoxy-carbonyl, carboxy, carboxy-C1-C6-alkylcarbonyl, carboxy-C2-C6-alkenylcarbonyl, amino, halogen, hydroxy, nitro, cyano, azido, phenyl or benzyloxy, R2 denotes hydrogen, C1-C6 alkyl, C1-C6 alkoxy, cyano, amino or hydroxy X denotes oxygen, sulphur or NR2 and Y denotes oxygen or sulphur as well as tautomers, enantiomers and diastereomers thereof and their physiologically tolerated salts, provided that R does not denote C1-C4 alkyl, allyl, benzyl, 4-bromophenylmethyl or phenyl if R1 represents an unsubstituted or substituted phenyl ring.
An aliphatic residue R in compounds of the general formula I denotes a straight-chained or branched alkyl, alkenyl or alkinyl residue with 1-9, preferably 2-7 carbon atoms such as e.g. a propyl, isopropyl, butyl, isobutyl, pentyl, hexyl or heptyl residue. C2-C7 alkenyl and alkinyl residues come into consideration as unsaturated residues and preferably C2-C5 such as an allyl, dimethylallyl, butenyl, isobutenyl, pentenyl or propinyl residue. Cyclopentyl and cyclohexyl are 21~8231 preferably used as the C3-C8 cycloalkyl residue. In the case of C1-C6 alkoxyalkyl, C1-C6 alkylmercaptoalkyl, aminoalkyl, C1-C6 alkylaminoalkyl, C1-C6-dialkylamino-alkyl and carboxyalkyl, the alkyl residue has 1 - 6 carbon atoms, preferably 1 - 3 carbon atoms. In the case of C3-C8 cycloalkylalkyl, phenyl-C1-C3-alkyl and pyridoxyl-C1-C3-alkyl, cyclopentylmethyl, benzyl, phenethyl, pyridylmethyl and pyridylethyl are preferred.
If R denotes a phenyl ring this can be substituted once, twice or three times. The substituents can independently of one another be in the o, m or p position.
A carbocyclic ring with 7-15 C atoms can be monocyclic, bicyclic or tricyclic and each can have 5 or 6 C atoms per ring. This ring can be saturated, unsaturated, partially saturated or aromatic. The following ring systems are mentioned as examples: the naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, acenaphthylenyl, norbornyl, adamantyl ring or a C3-C7 cycloalkyl or C5-C8 cycloalkenyl group. In addition the carbocyclic ring can be monosubstituted or disubstituted in which the substituents can, independently of each other, be in the o or m position and are selected from the group comprising C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylmercapto, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C2-C6 alkenyl, C2-C6 alkinyl, C3-C6 alkenyloxy, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkylcarbonyl-amino, C1-C6 alkylaminocarbonyl, C1-C6 alkoxycarbonyl, amino, hydroxy, nitro, azido, trifluoromethyl, cyano or halogen.
The heterocyclic monocyclic, bicyclic or tricyclic ring systems of the residue R contain 5 or 6 carbon atoms per ~168231 ring in which 1-4 or 1-5 C atoms can be substituted by the heteroatoms oxygen, sulphur and/or nitrogen. The ring systems can be aromatic, or partially or completely hydrogenated. The following ring systems are mentioned as examples: the pyridine, pyrimidine,-pyridazine, pyrazine, triazine, pyrrole, pyrazole, imidazole, triazole, thiazole, oxazole, isoxazole, oxadiazole, furazan, furan, thiophene, indole, quinoline, isoquinoline, coumarone, thionaphthene, benzoxazole, benzthiazole, indazole, benzimidazole, benztriazole, chromene, phthalazine, quinazoline, quinoxaline, methylenedioxy-benzene, carbazole, acridine, phenoxazine, phenothiazine, phenazine or purine system in which the unsaturated or aromatic carbocycles and heterocycles can be partially or completely hydrogenated. The heterocyclic ring system can in addition be monosubstituted or disubstituted, the substituents being independently of one another preferably in the o or m position.
R preferably denotes unsubstituted phenyl or phenyl which is substituted once or twice by C1-C6 alkyl, Cl-C6 alkoxy, C1-C6 alkylmercapto, Cl-C6 alkylsulfinyl, Cl-C6 alkylsulfonyl, C2-C4 alkenyl, C2-C6 alkinyl, C3-C4 alkenyloxy, Cl-C6 alkylamino, Cl-C6 dialkylamino, Cl-C6 alkylcarbonylamino, Cl-C6 alkylaminocarbonyl, Cl-C6 alkoxycarbonyl, amino, hydroxy, nitro, azido, trifluoromethyl, cyano or halogen. The "alkyl" moieties of the said substituents preferably contain up to three carbon atoms.
Heterocyclic ring systems and the hetaryl residues are preferably pyrrole, imidazole, furan, thiophene, pyridine, pyrimidine, thiazole, triazine, indole, quinoline, isoquinoline, coumarone, thionaphthene, ~168231 benzimidazole, quinazoline, methylenedioxybenzene, ethylenedioxybenzene, carbazole, acridine and phenothiazine wherein the heterocyclic rings can be substituted once or twice by C1-C6 alkyl, Cl-C6 alkoxy, C1-C6 alkylmercapto, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C2-C4 alkenyl, C2-C6 alkinyl, C3-C6 alkenyloxy, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkylcarbonylamino, C1-C6 alkylaminocarbonyl, C1-C6 alkoxycarbonyl, amino, hydroxy, nitro, azido, trifluoromethyl, cyano or halogen. The "alkyl" moieties of the said substituents preferably contain up to three carbon atoms.
If R1 denotes a phenyl ring or an aromatic, heterocyclic ring these can preferably be substituted once or several times by C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkinyl, C1-C3 alkoxy, C1-C3 alkylmercapto, C1-C3 alkylamino, C1-C3 dialkylamino, C1-C3 alkoxycarbonyl, carboxyethyl-carbonyl, carboxyvinylcarbonyl, amino, halogen, hydroxy, cyano and azido and the aromatic heterocyclic ring can have 3-7 carbon atoms wherein up to 4 of these ring atoms can be substituted by the heteroatoms oxygen, sulphur or/and nitrogen. The following heterocycles are mentioned as examples: the furan, oxazole, isoxazole, oxadiazole, triazole, pyridine, pyridazine, pyrimidine or pyrazine ring.
Particularly preferred residues for R are C3-C6 alkyl, C2-C6 alkenyl, C2-C4 alkinyl, benzyl, phenethyl, pyridylmethyl, pyridylethyl which are optionally monosubstituted or disubstituted with C1-C3 alkyl, C1-C3 alkoxy or halogen, phenyl which is monosubstituted or disubstituted by C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylmercapto, allyl, allyloxy, C1-C3 alkylamino, di-C1-C3 alkylamino, amino, hydroxy, azido, trifluoromethyl, ;~168231 cyano or halogen or phenyl which is trisubstituted by methyl or halogen, naphthyl, anthracenyl, indenyl, acenaphthylenyl, phenanthrenyl, adamantyl, cyclohexyl, cyclohexenyl, furyl, thienyl, pyridyl, pyrimidinyl, thiazolyl, indolyl, quinolinyl, benzimidazolyl, methylenedioxy-phenyl, carbazolyl and phenothiazinyl and derivatives of the aforementioned carbocyclic or heterocyclic rings that are monosubstituted or disubstituted by methyl or halogen.
Particularly preferred residues for Rl are phenyl and aromatic rings containing nitrogen with 5-6 ring atoms which are substituted once or several times with hydrogen, methyl, ethyl, isopropyl, allyl, methoxy, ethoxy, methylmercapto, ethylmercapto, methylamino, methoxycarbonyl, ethoxycarbonyl, carboxyvinylcarbonyl, amino, azido, cyano, hydroxy and halogen in which chlorine and bromine are particularly preferred for halogen.
Hydrogen, amino and hydroxy are particularly preferred for R2.
Oxygen and sulphur come into especially preferable consideration for X.
Y preferably denotes sulphur.
The compounds of the general formula I according to the invention are produced according to processes known from the literature by reacting isocyanates or thioisocyanates of the general formula II
21~8231 Rl - N = C = X (II) in which Rl has the meaning stated above and X is oxygen or sulphur with isoureas or isothioureas of the general formula III
R2N=C - Y - R (III) in which R, R2 and Y have the meanings stated above, in a suitable inert solvent at room temperature to reflux temperature optionally in the presence of a base such as triethylamine and if desired compounds of the formula I
are subsequently converted into other compounds of formula I and subsequently purified chromatographically or by recrystallization.
The additional conversion of compounds of formula I into other compounds of formula I relates for example to the production of derivatives of the general formula I in which X represents the residue NR2. These compounds are produced by reacting compounds of the general formula I
in which X=S or S denotes alkyl with amines of formula H2NR2 in a polar solvent optionally under pressure or in the presence of a carbodiimide at temperatures between 0C and the boiling point of the solvent.
The pharmaceutical agents contain at least one compound of formula I for the treatment of viral infections and can be administered enterally or parenterally in a liquid or solid form. In this case the usual forms of administration come into consideration such as for example tablets, capsules, coated tablets, syrups, solutions or suspensions. Water is preferably used as the injection medium which contains the usual additives for injection solutions such as stabilizing agents, solubilizers and buffers. Such additives are for example tartrate and citrate buffer, ethanol, complexing agents such as ethylenediaminetetraacetic acid and non-toxic salts thereof, high-molecular polymers such as liquid polyethylene oxide to regulate viscosity. Liquid carrier substances for injection solutions have to be sterile and are preferably dispensed into ampoules. Solid carriers are for example starch, lactose, mannitol, methylcellulose, talcum, highly dispersed silicic acids, higher molecular fatty acids such as stearic acid, gelatin, agar-agar, calcium phosphate, magnesium stearate, animal or vegetable fats, solid high-molecular polymers such as polyethylene glycols etc.. Preparations which are suitable for oral applications can if desired, contain flavourings and sweeteners.
The dose can depend on various factors such as mode of administration, species, age or individual condition.
The compounds according to the invention are usually administered in amounts of 0.1 - 100 mg, preferably 0.2 - 80 mg per day and per kg body weight. The daily dose is preferably divided into 2 to 5 applications in which 1-2 tablets having a content of active substance of 0.5 - 500 mg are administered at each application.
The tablets can also be retarded by which means the number of applications is reduced to 1-3 times per day.
The content of active substance in retarded tablets can be 2 - 1000 mg. The active substance can also be administered by continuous infusion in which case amounts of 5 - 1000 mg per day are usually adequate. The pharmaceutical agents can also be administered combined with other antiviral agents such as AZT.
~16~231 In addition to the compounds mentioned in the examples and those derived by combining all meanings of substituents stated in the claims, the following compounds of formula I come into consideration within the sense of the present invention which can be present as racemic mixtures or in an optical active form or as pure R and S enantiomers:
1. N-(phenylaminothiocarbonyl)thiocarbimidinic acid-2-(4-methylpentyl)ester 2. N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid 2-(4-methylpentyl) ester 3. N-(3-fluorophenylaminothiocarbonyl)thiocarbimidinic acid 2-(4-methylpentyl) ester 4. N-(4-dimethylaminophenylaminothiocarbonyl)thio-carbimidinic acid 2-(4-methylpentyl) ester 5. N-(4-hydroxycarbonylphenylaminothiocarbonyl)thio-carbimidinic acid 2-(4-methylpentyl) ester 6. N-(4-hydroxysulfonylphenylaminothiocarbonyl)thio-carbimidinic acid 2-(4-methylpentyl) ester 7. N-(4-carboxyvinylcarbonylphenylaminothiocarbonyl)-thio-carbimidinic acid 2-(4-methylpentyl) ester 8. N-(4-methoxyphenylaminothiocarbonyl)thio-carbimidinic acid 2-(4-methylpentyl) ester ~168231 9. N-(3-trifluoromethylphenylaminothiocarbonyl)thio-carbimidinic acid 2-(4-methylpentyl) ester 10. N-(2-bromophenylaminothiocarbonyl)thiocarbimidinic acid 2-(4-methylpentyl) ester 11. N-(4-methylphenylaminothiocarbonyl)thiocarbimidinic acid 2-(4-methylpentyl) ester 12. N-(4-nitrophenylaminothiocarbonyl)thiocarbimidinic acid 2-(4-methylpentyl) ester 13. N-(4-isopropylphenylaminothiocarbonyl)thio-carbimidinic acid 2-(4-methylpentyl) ester 14. N-(3-cyanophenylaminothiocarbonyl)thiocarbimidinic acid 2-(4-methylpentyl) ester 15. N-(4-methylsulfonylphenylaminothiocarbonyl)thio-carbimidinic acid 2-(4-methylpentyl) ester 16. N-(2-pyridylaminothiocarbonyl)thiocarbimidinic acid 2-(4-methylpentyl) ester 17. N-(3-pyridylaminothiocarbonyl)thiocarbimidinic acid 2-(4-methylpentyl) ester 18. N-(4-pyridylaminothiocarbonyl)thiocarbimidinic acid 2-(4-methylpentyl) ester 19. N-[(5-bromo-2-pyridyl)aminothiocarbonyl]-thio-carbimidinic acid 2-(4-methylpentyl) ester ~1~3231 20. N-(2-thienylaminothiocarbonyl)-thiocarbimidinic acid 2-(4-methylpentyl) ester 21. N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid methyl ester 22. N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid ethyl ester 23. N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid benzyl ester 24. N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid (2-chlorobenzyl) ester 25. N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid cyclohexyl ester 26. N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid (4(5)-imidazolylmethyl) ester 27. N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid hexyl ester 28. N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid (2-pyridylethyl) ester 29. N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid (3-chlorobenzyl) ester 30. N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid (4-chlorobenzyl) ester 31. N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid (2-aminoethyl) ester 32. N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid (2,5-dihydroxyphenyl) ester -33. N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid (2-carboxyethyl) ester 34. N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid isopropentyl ester 35. N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid n-butyl ester 36. N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid (2-dimethylaminoethyl) ester 37. N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid (3-dimethylaminopropyl) ester 38. N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid (2-pyridyl) ester 39. N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid (3-methyl-2-pyridyl) ester 40. N-(phenylaminocarbonyl)thiocarbimidinic acid methyl ester 41. N-(phenylaminocarbonyl)thiocarbimidinic acid benzyl ester ~1~3231 42. N-(phenylaminocarbonyl)thiocarbimidinic acid phenyl ester 43. N-(phenylaminocarbonyl)thiocarbimidinic acid 2-(4-methylpentyl) ester 44. N-(phenylaminothiocarbonyl)carbimidinic acid ethyl ester 45. N-(phenylaminothiocarbonyl)carbimidinic acid allyl ester 46. N-(phenylaminothiocarbonyl)carbimidinic acid (3-methylphenyl) ester 47. N-(phenylaminothiocarbonyl)carbimidinic acid 2-(5-methylpyridyl) ester Example N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid 2-~4-methylpentyl)ester a) 22.83 g (0.3 mol) thiourea and 55 g (0.33 mol) 2-bromo-4-methylpentane are heated for 24 hours in 40 ml ethanol under reflux. The solvent was subsequently concentrated by evaporation, the residue was admixed with 250 ml ether and suction filtered.
After recrystallizing from acetone 52 g 2-(4-methyl-pentyl)isothiuronium bromide is obtained with a ~1~8231 melting point of 143C.
b) 2.65 g (11 mmol) 2-(4-methylpentyl)isothiuronium bromide (example la), 1.69 g (10 mmol) 4-chloro-phenylisothiocyanate and 1.12 g (11 mmol) triethylamine were stirred in 20 methylene chloride for 5 hours at 25C. Subsequently the organic phase was washed with 1 N cold hydrochloric acid and hydrogen carbonate solution and concentrated by evaporation. The residue was recrystallized from isopropanol/isohexane (1:3). 2.1 g of the title compound with a melting point of 117-119C was obtained.
Exampl~ 2 The following compounds are obtained analogously to example 1:
a) N-(phenylaminothiocarbonyl)thiocarbimidinic acid 2-(4-methylpentyl) ester with a melting point of 95-96C.
b) N-(3-fluorophenylaminothiocarbonyl)thiocarbimidinic acid 2-(4-methylpentyl) ester with a melting point of 80-95C.
c) N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid methyl ester with a melting point of 145-146C.
d) N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid ethyl ester with a melting point of 125-126C.
i~168231 e) N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid benzyl ester with a melting point of 133-135C.
f) N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid cyclohexyl ester with a melting point of 144-146C.
g) N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid 3-chlorobenzyl ester with a melting point of 123-124C.
h) N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid 4-chlorobenzyl ester with a melting point of 147-149C.
i) N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid hexyl ester with a melting point of 106-107C.
j) N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid butyl ester with a melting point of 126-128C.
k) N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid 2-methylallyl ester with a melting point of 139-141C.
l) N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid 2-(2-pyridyl)ethyl ester with a melting point of 132-134C.
m) N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid 2-(4-morpholino)ethyl ester with a melting point of 121-123C.
~168231 n) N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid phenyl ester with a melting point of 127-129C.
o) N-(4-chlorophenylaminothiocarbonyl)thiocarbimidinic acid (4-methylpyridin-2-yl)-methyl ester with a melting point of 148-149C.
p) N-[(4-chlorophenyl)methylaminothiocarbonyl]thio-carbimidinic acid 2-(4-methylpentyl) ester as an oil.
Rf value: 0.7 (toluene:dioxane:water) q) N-[2-(4-chlorophenyl)ethylaminothiocarbonyl]thio-carbimidinic acid 2-(4-methylpentyl) ester as an oil.
Rf value: 0.25 (toluene) r) N-(4-aminosulfonylphenylaminothiocarbonyl)thio-carbimidinic acid 2-(4-methylpentyl) ester with a melting point of 113-116C.
s) N-(4-carboxyphenylaminothiocarbonyl)thiocarbimidinic acid 2-(4-methylpentyl) ester with a melting point of 187-191C.
t) N-(phenylaminothiocarbonyl)thiocarbimidinic acid 1-(2-methyl)phenethyl ester with a melting point of 84-86C.
Example 3 N-(phenylaminocarbonyl)thiocsrbimidinic acid 2-~4-methylpentyl) ester 2.73 g of the title compound is obtained analogously to example lb as a colourless resin ~TLC, mobile solvent:
toluene:dioxane:water (90:20:0.2), Rf=0.64 from 2.65 g (11 mmol) 2-(4-methylpentyl)isothiuronium bromide, 1.19 g (10 mmol) phenylisocyanate and 1.12 g (11 mmol) triethylamine in 20 ml methylene chloride.
~xample 4 Antiviral efficacy The antiviral efficacy of some selected substances was examined in vivo as well as in vitro (inhibition of reverse transcriptase RT).
a) MT2/MTT test system (in vivo) MT2 cells are infected with HIV-1 (HTLV III B
isolate). After a 7 day incubation a MTT test was carried out which determined the vitality of the cells. The vitality of the cells correlates with the extent of virus production. IC50 values are stated in the following table i.e. that concentration of the substances that causes a 50 % inhibition.
21~8~31 b) Inhibition of RT (in vitro) The extent of the inhibition of RT activity is determined in a non-radioactive microtitre plate test. The amount of nucleotides incorporated into the DNA to be synthesized is determined photometrically.
IC50 values (ug/ml) Example No MT2 RT
1 0.6 0.6 2 b 3.3 1.0 2 e < 3 2.45 2 f < 3 0.103 2 g < 3 0.33 2 j < 3 0.76 2 n - 0.9
Claims (11)
1. Pharmaceutical agents containing at least one (thio)carbimidinic acid derivative of formula I as the active substance (I) in which R denotes a straight-chained or branched, saturated or unsaturated aliphatic residue with 1-9 carbon atoms, C3-C8 cycloalkyl, C1-C6 alkoxyalkyl, C1-C6 alkylmercapto-C1-C6-alkyl, amino-C1-C6-alkyl, C1-C6 alkylamino-C1-C6-alkyl, C1-C6 dialkylamino-C1-C6-alkyl, carboxy-C1-C6-alkyl, C3-C8 cycloalkyl-C1-C6-alkyl; substituted phenyl-C1-C6-alkyl;
substituted pyridyl-C1-C6-alkyl;
phenyl which can be optionally substituted once or several times by C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylmercapto, C1-C6 alkylsulfinyl, C1-C6 alkyl-sulfonyl, C2-C6 alkenyl, C2-C6 alkinyl, C2-C6 alkenyloxy, C2-C6 alkenylmercapto, C2-C6 alkinyloxy, C2-C6 alkinylmercapto, amino, C1-C6 alkylamino, di-C1-C6 alkylamino, C1-C6 alkylcarbonylamino, C1-C6 alkylaminocarbonyl, C1-C6 alkoxycarbonyl, hydroxy, benzyloxy, phenylmercapto, phenyloxy, nitro, cyano, halogen, trifluoromethyl, azido, formylamino, carboxy or phenyl;
can represent a carbocyclic monocyclic, bicyclic or tricyclic residue with 7-15 C atoms or a heterocyclic monocyclic, bicyclic or tricyclic ring system in which the unsaturated or aromatic carbocycles and heterocycles can be partially or completely hydrogenated, R1 can be phenyl, phenyl C1-C6-alkyl, hetaryl or hetaryl-C1-C6-alkyl, wherein the heteroatoms can be the same or different and denote oxygen, sulphur or nitrogen which can be optionally substituted once or several times by a straight-chained or branched, saturated or unsaturated C1-C6 or C2-C6 alkyl residue, C1-C6 alkoxy, C1-C6 alkylmercapto, C1-C6 alkyl-sulfinyl, C1-C6 alkylsulfonyl, C1-C6 alkyl-amino, C1-C6 dialkylamino, C1-C6 alkoxycarbonyl, carboxy, carboxy-C1-C6-alkylcarbonyl, carboxy-C2-C6-alkenylcarbonyl, amino, halogen, hydroxy, nitro, cyano, azido, phenyl or benzyloxy, R2 denotes hydrogen, C1-C6 alkyl, C1-C6 alkoxy, cyano, amino or hydroxy X denotes oxygen, sulphur or NR2 and Y denotes oxygen or sulphur as well as tautomers, enantiomers and diastereomers thereof and their physiologically tolerated salts, provided that R1 does not represent a 2,6 methyl-substituted phenyl ring when X = O, Y = S, R =
methyl and R2 = H.
substituted pyridyl-C1-C6-alkyl;
phenyl which can be optionally substituted once or several times by C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylmercapto, C1-C6 alkylsulfinyl, C1-C6 alkyl-sulfonyl, C2-C6 alkenyl, C2-C6 alkinyl, C2-C6 alkenyloxy, C2-C6 alkenylmercapto, C2-C6 alkinyloxy, C2-C6 alkinylmercapto, amino, C1-C6 alkylamino, di-C1-C6 alkylamino, C1-C6 alkylcarbonylamino, C1-C6 alkylaminocarbonyl, C1-C6 alkoxycarbonyl, hydroxy, benzyloxy, phenylmercapto, phenyloxy, nitro, cyano, halogen, trifluoromethyl, azido, formylamino, carboxy or phenyl;
can represent a carbocyclic monocyclic, bicyclic or tricyclic residue with 7-15 C atoms or a heterocyclic monocyclic, bicyclic or tricyclic ring system in which the unsaturated or aromatic carbocycles and heterocycles can be partially or completely hydrogenated, R1 can be phenyl, phenyl C1-C6-alkyl, hetaryl or hetaryl-C1-C6-alkyl, wherein the heteroatoms can be the same or different and denote oxygen, sulphur or nitrogen which can be optionally substituted once or several times by a straight-chained or branched, saturated or unsaturated C1-C6 or C2-C6 alkyl residue, C1-C6 alkoxy, C1-C6 alkylmercapto, C1-C6 alkyl-sulfinyl, C1-C6 alkylsulfonyl, C1-C6 alkyl-amino, C1-C6 dialkylamino, C1-C6 alkoxycarbonyl, carboxy, carboxy-C1-C6-alkylcarbonyl, carboxy-C2-C6-alkenylcarbonyl, amino, halogen, hydroxy, nitro, cyano, azido, phenyl or benzyloxy, R2 denotes hydrogen, C1-C6 alkyl, C1-C6 alkoxy, cyano, amino or hydroxy X denotes oxygen, sulphur or NR2 and Y denotes oxygen or sulphur as well as tautomers, enantiomers and diastereomers thereof and their physiologically tolerated salts, provided that R1 does not represent a 2,6 methyl-substituted phenyl ring when X = O, Y = S, R =
methyl and R2 = H.
2. Pharmaceutical agents as claimed in claim 1, wherein R represents a monocyclic, bicyclic or tricyclic carbocyclic ring with 7-15 C atoms selected from the group comprising naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, acenaphthylenyl, norbornyl, adamantyl, C3 - C7 cycloalkyl or C5-C8 cycloalkenyl ring in which the carbocyclic ring can be unsubstituted or substituted by one or several substituents selected from the group comprising a C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylmercapto, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C2-C6 alkenyl, C2-C6 alkinyl, C3-C6 alkenyloxy, C1-C6 alkylamino, C1-C6 dialkyl-amino, C1-C6 alkylcarbonylamino, C1-C6 alkylamino-carbonyl, C1-C6 alkoxycarbonyl, amino, hydroxy, nitro, azido, trifluoromethyl, cyano or halogen.
3. Pharmaceutical agents as claimed in claim 1, wherein R denotes a heterocyclic monocyclic, bicyclic or tricyclic ring selected from the group comprising a pyridine, pyrimidine, pyridazine, pyrazine, triazine, pyrrole, pyrazole, imidazole, triazole, thiazole, oxazole, isoxazole, oxadiazole, furazan, furan, thiophene, indole, quinoline, isoquinoline, coumarone, thionaphthene, - 26a -benzoxazole, benzthiazole, indazole, benzimidazole, benztriazole, chromene, phthalazine, quinazoline, quinoxaline, methylene-dioxybenzene, carbazole, acridine, phenoxazine, phenothiazine, phenazine or purine system in which these can be partially or completely hydrogenated and these rings are unsubstituted or substituted by one or several substituents selected from the group comprising C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylmercapto, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C2-C6 alkenyl, C2-C6 alkinyl, C3-C6 alkenyloxy, C1-C6 alkylamino, C1-C6 dialkylamino, C1-C6 alkylcarbonylamino, C1-C6 alkylaminocarbonyl, C1-C6 alkoxycarbonyl, amino, hydroxy, nitro, azido, trifluoromethyl, cyano or halogen.
4. Pharmaceutical agents as claimed in claim 3, wherein R denotes a pyrrole, imidazole, furan, thiophene, pyridine, pyrimidine, thiazole, triazine, indole, quinoline, isoquinoline, coumarone, thionaphthene, benzimidazole, quinazoline, methylenedioxybenzene, ethylenedioxybenzole, carbazole, acridine or phenothiazine ring which can be substituted once or twice by C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylmercapto, C1-C3 alkylsulfinyl, C1-C3 alkylsulfonyl, C2-C4 alkenyl, C2-C3 alkinyl, C3-C4 alkenyloxy, C1-C3 alkylamino, C1-C3 dialkylamino, C1-C3 alkylcarbonylamino, C1-C3 alkylaminocarbonyl, C1-C3 alkoxycarbonyl, amino, hydroxy, nitro, azido, trifluoromethyl, cyano or halogen.
5. Pharmaceutical agents as claimed in claim 1, wherein R denotes C3-C6 alkyl, C2-C6 alkenyl, C2-C4 alkinyl, benzyl, phenethyl, pyridylmethyl, pyridylethyl which is optionally monosubstituted or disubstituted by C1-C3 alkyl, C1-C3 alkoxy or halogen; phenyl which is optionally substituted by C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylmercapto, allyl, allyloxy, C1-C3 alkylamino, di-C1-C3 alkylamino, amino, hydroxy, azido, trifluoromethyl, cyano or halogen.
6. Pharmaceutical agent as claimed in claims 1-5, wherein R2 denotes hydrogen, amino or hydroxy.
7. Pharmaceutical agent as claimed in claims 1-6, wherein X denotes oxygen or sulphur.
8. Pharmaceutical agent as claimed in claims 1-7, wherein Y denotes sulphur.
9. Compounds of formula I
(I), in which R denotes a straight-chained or branched, saturated or unsaturated C1-C9 or C2-C9 alkyl, C3-C8 cyclo-alkyl, C1-C6 alkoxyalkyl, C1-C6 alkylmercaptoalkyl, aminoalkyl, C1-C6 alkylaminoalkyl, C1-C6 dialkyl-aminoalkyl, carboxyalkyl, C3-C8 cycloalkylalkyl;
substituted phenyl-C1-C6-alkyl, substituted pyridyl-C1-C6-alkyl, phenyl which can be optionally substituted once or several times by C1-C6-alkyl, C1-C6 alkoxy, C1-C6 alkylmercapto, C1-C6 alkyl-sulfinyl, C1-C6 alkylsulfonyl, C2-C6 alkenyl, C2-C6 alkinyl, C2-C6 alkenyloxy, C2-C6 alkenylmercapto, C2-C6 alkinyloxy, C2-C6 alkinylmercapto, amino, C1-C6 alkylamino, di-C1-C6 alkylamino, C1-C6 alkyl-carbonylamino, C1-C6 alkylaminocarbonyl, C1-C6 alkoxycarbonyl, hydroxy, benzyloxy, phenylmercapto, phenyloxy, nitro, cyano, halogen, trifluoromethyl, azido, formylamino, carboxy or phenyl; it can represent naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, acenaphthylenyl, norbornyl, adamantyl, C3-C7 cycloalkyl, C5-C8 cycloalkenyl or a heterocyclic monocyclic, bicyclic or tricyclic system such as the pyridine, pyrimidine, pyridazine, pyrazine, triazine, pyrrole, pyrazole, imidazole, triazole, thiazole, oxazole, isoxazole, oxadiazole, furazan, furan, thiophene, indole, quinoline, isoquinoline, coumarone, thionaphthene, benzoxazole, benzthiazole, indazole, benzimidazole, benztriazole, chromene, phthalazine, quinazoline, quinoxaline, methylenedioxybenzene, carbazole, acridine, phenoxazine, phenothiazine, phenozine or purine system in which the unsaturated or aromatic carbocycles or heterocycles can be partially or completely hydrogenated.
R1 can be phenyl, phenyl C1-C6-alkyl, hetaryl or hetaryl-C1-C6 alkyl, wherein the heteroatoms can be the same or different and denote oxygen, sulphur or nitrogen, which can be optionally substituted once or several times by a straight-chained or branched, saturated or unsaturated C1-C6 or C2-C6 alkyl residue, C1-C6 alkoxy, C1-C6 alkylmercapto, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 alkyl-amino, C1-C6 dialkylamino, C1-C6 alkoxycarbonyl, carboxy, carboxyalkylcarbonyl, carboxyalkenyl-carbonyl, amino, halogen, hydroxy, nitro, cyano, azido, phenyl or benzyloxy, R2 denotes hydrogen, C1-C6 alkyl, C1-C6 alkoxy, cyano, amino or hydroxy X denotes oxygen, sulphur or NR2 and Y denotes oxygen or sulphur as well as tautomers, enantiomers and diastereomers thereof and their physiologically tolerated salts, provided that R does not denote C1-C4 alkyl, allyl, benzyl, 4-bromophenylmethyl or phenyl if R1 represents an unsubstituted or substituted phenyl ring.
(I), in which R denotes a straight-chained or branched, saturated or unsaturated C1-C9 or C2-C9 alkyl, C3-C8 cyclo-alkyl, C1-C6 alkoxyalkyl, C1-C6 alkylmercaptoalkyl, aminoalkyl, C1-C6 alkylaminoalkyl, C1-C6 dialkyl-aminoalkyl, carboxyalkyl, C3-C8 cycloalkylalkyl;
substituted phenyl-C1-C6-alkyl, substituted pyridyl-C1-C6-alkyl, phenyl which can be optionally substituted once or several times by C1-C6-alkyl, C1-C6 alkoxy, C1-C6 alkylmercapto, C1-C6 alkyl-sulfinyl, C1-C6 alkylsulfonyl, C2-C6 alkenyl, C2-C6 alkinyl, C2-C6 alkenyloxy, C2-C6 alkenylmercapto, C2-C6 alkinyloxy, C2-C6 alkinylmercapto, amino, C1-C6 alkylamino, di-C1-C6 alkylamino, C1-C6 alkyl-carbonylamino, C1-C6 alkylaminocarbonyl, C1-C6 alkoxycarbonyl, hydroxy, benzyloxy, phenylmercapto, phenyloxy, nitro, cyano, halogen, trifluoromethyl, azido, formylamino, carboxy or phenyl; it can represent naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, acenaphthylenyl, norbornyl, adamantyl, C3-C7 cycloalkyl, C5-C8 cycloalkenyl or a heterocyclic monocyclic, bicyclic or tricyclic system such as the pyridine, pyrimidine, pyridazine, pyrazine, triazine, pyrrole, pyrazole, imidazole, triazole, thiazole, oxazole, isoxazole, oxadiazole, furazan, furan, thiophene, indole, quinoline, isoquinoline, coumarone, thionaphthene, benzoxazole, benzthiazole, indazole, benzimidazole, benztriazole, chromene, phthalazine, quinazoline, quinoxaline, methylenedioxybenzene, carbazole, acridine, phenoxazine, phenothiazine, phenozine or purine system in which the unsaturated or aromatic carbocycles or heterocycles can be partially or completely hydrogenated.
R1 can be phenyl, phenyl C1-C6-alkyl, hetaryl or hetaryl-C1-C6 alkyl, wherein the heteroatoms can be the same or different and denote oxygen, sulphur or nitrogen, which can be optionally substituted once or several times by a straight-chained or branched, saturated or unsaturated C1-C6 or C2-C6 alkyl residue, C1-C6 alkoxy, C1-C6 alkylmercapto, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 alkyl-amino, C1-C6 dialkylamino, C1-C6 alkoxycarbonyl, carboxy, carboxyalkylcarbonyl, carboxyalkenyl-carbonyl, amino, halogen, hydroxy, nitro, cyano, azido, phenyl or benzyloxy, R2 denotes hydrogen, C1-C6 alkyl, C1-C6 alkoxy, cyano, amino or hydroxy X denotes oxygen, sulphur or NR2 and Y denotes oxygen or sulphur as well as tautomers, enantiomers and diastereomers thereof and their physiologically tolerated salts, provided that R does not denote C1-C4 alkyl, allyl, benzyl, 4-bromophenylmethyl or phenyl if R1 represents an unsubstituted or substituted phenyl ring.
10. Process for the production of compounds as claimed in claim 9, wherein isocyanates or thioisocyanates of the general formula II
R1 - N = C = X (II) in which R1 has the meaning stated above and X is oxygen or sulphur are reacted with isoureas or isothioureas of the general formula III
(III) in which R, R2 and Y have the meanings stated above, in a suitable inert solvent at room temperature to reflux temperature they are isolated and subsequently compounds of formula I are optionally converted into other compounds of formula I.
R1 - N = C = X (II) in which R1 has the meaning stated above and X is oxygen or sulphur are reacted with isoureas or isothioureas of the general formula III
(III) in which R, R2 and Y have the meanings stated above, in a suitable inert solvent at room temperature to reflux temperature they are isolated and subsequently compounds of formula I are optionally converted into other compounds of formula I.
11. Use of compounds of formula I as claimed in claim 1 or 9 for the production of pharmaceutical agents for the treatment of diseases caused by viral or retroviral infections.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4325741.0 | 1993-07-31 | ||
| DE4325741A DE4325741A1 (en) | 1993-07-31 | 1993-07-31 | (Thio) carbamidic acid derivatives and medicaments containing them |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2168231A1 true CA2168231A1 (en) | 1995-02-09 |
Family
ID=6494161
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002168231A Abandoned CA2168231A1 (en) | 1993-07-31 | 1994-07-26 | (thio)carbimidinic acid derivatives and pharmaceutical agents containing them |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0711275B1 (en) |
| JP (1) | JPH09500885A (en) |
| AT (1) | ATE165084T1 (en) |
| AU (1) | AU7460794A (en) |
| CA (1) | CA2168231A1 (en) |
| DE (2) | DE4325741A1 (en) |
| WO (1) | WO1995004034A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102009056187A1 (en) | 2008-11-28 | 2010-07-15 | Basf Se | Polyester resin obtained by polycondensation of mixture comprising polyol, polycarbonic acid, 2-propylheptanoic acid glycidyl ester and/or 4-methyl-2-propylheptanoic acid glycidyl ester, useful e.g. in coating composition |
-
1993
- 1993-07-31 DE DE4325741A patent/DE4325741A1/en not_active Withdrawn
-
1994
- 1994-07-26 CA CA002168231A patent/CA2168231A1/en not_active Abandoned
- 1994-07-26 JP JP7505555A patent/JPH09500885A/en active Pending
- 1994-07-26 EP EP94924289A patent/EP0711275B1/en not_active Expired - Lifetime
- 1994-07-26 AT AT94924289T patent/ATE165084T1/en not_active IP Right Cessation
- 1994-07-26 WO PCT/EP1994/002461 patent/WO1995004034A1/en active IP Right Grant
- 1994-07-26 DE DE59405726T patent/DE59405726D1/en not_active Expired - Fee Related
- 1994-07-26 AU AU74607/94A patent/AU7460794A/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| DE4325741A1 (en) | 1995-02-02 |
| JPH09500885A (en) | 1997-01-28 |
| DE59405726D1 (en) | 1998-05-20 |
| EP0711275A1 (en) | 1996-05-15 |
| WO1995004034A1 (en) | 1995-02-09 |
| ATE165084T1 (en) | 1998-05-15 |
| EP0711275B1 (en) | 1998-04-15 |
| AU7460794A (en) | 1995-02-28 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |