US3262930A - Novel 5-nitro-furfurylidene-(2) derivatives and process for producing the same - Google Patents

Novel 5-nitro-furfurylidene-(2) derivatives and process for producing the same Download PDF

Info

Publication number: US3262930A
Authority: US; United States
Prior art keywords: nitro; dioxide; furfurylidene; novel; derivatives
Prior art date: 1962-11-23
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Expired - Lifetime

Application number

US323225A

Other languages

English (en)

Inventor

Herlinger Heinz

Mayer Karl-Heinrich

Petersen Siegfried

Bock Marianne

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Bayer AG

Original Assignee

Bayer AG

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1962-11-23

Filing date

1963-11-13

Publication date

1966-07-26

1963-11-13 Application filed by Bayer AG filed Critical Bayer AG

1966-07-26 Application granted granted Critical

1966-07-26 Publication of US3262930A publication Critical patent/US3262930A/en

1983-07-26 Anticipated expiration legal-status Critical

Status Expired - Lifetime legal-status Critical Current

Links

238000000034 method Methods 0.000 title description 3
150000001875 compounds Chemical class 0.000 claims description 14
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
241001465754 Metazoa Species 0.000 description 10
230000000694 effects Effects 0.000 description 10
241000223109 Trypanosoma cruzi Species 0.000 description 7
-1 alkyl radicals Chemical class 0.000 description 5
238000002844 melting Methods 0.000 description 5
230000008018 melting Effects 0.000 description 5
OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
210000004369 blood Anatomy 0.000 description 4
239000008280 blood Substances 0.000 description 4
238000009835 boiling Methods 0.000 description 4
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
238000001953 recrystallisation Methods 0.000 description 3
238000012360 testing method Methods 0.000 description 3
206010001935 American trypanosomiasis Diseases 0.000 description 2
208000024699 Chagas disease Diseases 0.000 description 2
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
241000223104 Trypanosoma Species 0.000 description 2
230000000507 anthelmentic effect Effects 0.000 description 2
229940124339 anthelmintic agent Drugs 0.000 description 2
239000000921 anthelmintic agent Substances 0.000 description 2
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
230000015572 biosynthetic process Effects 0.000 description 2
238000006243 chemical reaction Methods 0.000 description 2
230000000052 comparative effect Effects 0.000 description 2
239000013078 crystal Substances 0.000 description 2
230000035876 healing Effects 0.000 description 2
229910052739 hydrogen Inorganic materials 0.000 description 2
239000001257 hydrogen Substances 0.000 description 2
125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
238000002347 injection Methods 0.000 description 2
239000007924 injection Substances 0.000 description 2
238000004519 manufacturing process Methods 0.000 description 2
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
239000007858 starting material Substances 0.000 description 2
238000003786 synthesis reaction Methods 0.000 description 2
YODQQARABJQLIP-UHFFFAOYSA-N thian-4-ol Chemical compound OC1CCSCC1 YODQQARABJQLIP-UHFFFAOYSA-N 0.000 description 2
231100000419 toxicity Toxicity 0.000 description 2
230000001988 toxicity Effects 0.000 description 2
238000011282 treatment Methods 0.000 description 2
125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
DVIPWDUJCAFPRK-UHFFFAOYSA-N 5-(2,5-dihydroxypentylsulfanyl)pentane-1,4-diol Chemical compound OCCCC(O)CSCC(O)CCCO DVIPWDUJCAFPRK-UHFFFAOYSA-N 0.000 description 1
241000699670 Mus sp. Species 0.000 description 1
GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
208000035415 Reinfection Diseases 0.000 description 1
UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
241000223107 Trypanosoma congolense Species 0.000 description 1
206010057362 Underdose Diseases 0.000 description 1
125000000217 alkyl group Chemical group 0.000 description 1
150000005840 aryl radicals Chemical class 0.000 description 1
239000007795 chemical reaction product Substances 0.000 description 1
238000002425 crystallisation Methods 0.000 description 1
230000008025 crystallization Effects 0.000 description 1
231100000676 disease causative agent Toxicity 0.000 description 1
238000004821 distillation Methods 0.000 description 1
238000011156 evaluation Methods 0.000 description 1
238000001914 filtration Methods 0.000 description 1
208000015181 infectious disease Diseases 0.000 description 1
239000000203 mixture Substances 0.000 description 1
239000003960 organic solvent Substances 0.000 description 1
230000003647 oxidation Effects 0.000 description 1
238000007254 oxidation reaction Methods 0.000 description 1
210000005259 peripheral blood Anatomy 0.000 description 1
239000011886 peripheral blood Substances 0.000 description 1
CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
239000001120 potassium sulphate Substances 0.000 description 1
238000002360 preparation method Methods 0.000 description 1
239000011541 reaction mixture Substances 0.000 description 1
239000011369 resultant mixture Substances 0.000 description 1
DUIOPKIIICUYRZ-UHFFFAOYSA-N semicarbazide Chemical compound NNC(N)=O DUIOPKIIICUYRZ-UHFFFAOYSA-N 0.000 description 1
239000000243 solution Substances 0.000 description 1
241000894007 species Species 0.000 description 1
238000007920 subcutaneous administration Methods 0.000 description 1
239000000126 substance Substances 0.000 description 1
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
231100000331 toxic Toxicity 0.000 description 1
231100000816 toxic dose Toxicity 0.000 description 1
230000002588 toxic effect Effects 0.000 description 1
201000002311 trypanosomiasis Diseases 0.000 description 1
238000005406 washing Methods 0.000 description 1
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- C07D307/56—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 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
- C07D307/70—Nitro radicals
- C07D307/71—Nitro radicals attached in position 5
- C07D307/72—Nitro radicals attached in position 5 with hydrocarbon radicals, substituted by nitrogen-containing radicals, attached in position 2
- C07D307/74—Nitro radicals attached in position 5 with hydrocarbon radicals, substituted by nitrogen-containing radicals, attached in position 2 by hydrazino or hydrazono or such substituted radicals
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D327/00—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms
- C07D327/02—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms one oxygen atom and one sulfur atom
- C07D327/06—Six-membered rings
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

the present invention relates, in general, to organic chemistry, and, more particularly, to certain novel 5- nitro-furfurylidene-(l) derivatives and a unique process for producing the same via the reaction of S-nitro-furfurol-(Z) with l-arninotetra-hydro-l,4-thiazine-4,4-dioxide. Additionally, the invention involves the use of the novel compounds of the invention as ant-helmintics of rather specific and unique activity as explained in greater detail hereinafter.
the compounds of the invention may be represented by the following structural formula wherein R represents hydrogen, from 1 to 4 lower (C C alkyl radicals, from 1 to 2 aralkyl radicals such as benzyl, or aryl radicals such as phenyl.
the indicated reaction of the l-aminotetrahydro-1,4-thiaZine-dioxide with S-ni-tro-furfurol is effected within an organic solvent medium in which both of the starting components are soluble, and in which the desired end-product is insoluble.
the compounds of the invention are distinguished by a low order of toxicity and high activity against Trypanosoma cruzi, the causative agent for the Chagas disease as well as other protozoa, e.g., Trypanosoma congolense and Trypanosoma bruceiaus.
the Chagas disease the South American form of trypanosomiasis, for example, the semicarbazide of 5-nitro furfurol-(2) has been used hereto-fore.
the compounds of the invention were investigated with white mice.
the animals were injected with Trypanosoma crwzi, and thereafter treated subcutaneously with the unit dosages indicated in Table I on four successive days, commencing one day after initial injection.
blood samples of the treated animals were examined microscopically for Trypanosoma cruzi at intervals of one day, commencing the sixth day after initial injection, and compared with untreated injected control animals of the same species.
the animals are treated with an insufficient dosage of the anthelmintics of the invention, the same number of trypanosomes are found in the blood as in that of the control animals designates no effect). If, on the other hand, effective doses of the preparation are administered to the animals, the blood is free of trypanosomes for a few days or even for weeks. With reference to Table I, the ultimate test result is indicated by the designation HE (healing efiect), provided the Trypanosoma cruzi cannot be detected within the peripheral blood of the test animals for four weeks or longer, and a re-infection takes a positive course.
HE heating efiect
RE recidivation efiect
T traces of effect
Example I Fifteen (15) grams of l-amino-tetrahydro-l,4-thiazine-4,4-dioxide were treated Within 150 milliliters of acetic acid with 14.1 grams of S-nitro-furfurol-(Z), and the mixture heated for a short time. Orange-red crystals of 1-(5-nitro-furfurylidene-amino)-1,4tetrahydrothiazine- 4,4-dioxide separated out at once which, following filtration via suction and washing with Water, were immediately found to be analytically pure. The melting point, following recrystallization from acetic acid, was found to be 191 C.
Example II 1 amino Z-methyI-tetrahydro-1,4-hydroxythiazine-4,4- dioxide, in amount of 15.4 grams, was dissolved in 100 milliliters of alcohol and 5 milliliters of acetic acid, and then added to a solution consisting of 14.1 grams of 5- nitro-furfurol-(2) within 100 milliliters of alcohol.
the production of the 1-amino-2-methyl-tetrahydro- 1,4 hydroxythiazine-dioxide used as the starting compound in the foregoing synthesis can be eflfected by (a) reacting Z-mercaptoethanol with propylene oxide in the presence of potassium hydroxide. 2-hydroxyethyl-Z-hydroxypropyl sulphide of boiling point 160 C. at 15 mm. Hg is thus obtained; (b) distillation of 2-hydroxyethyl-2- hydroxypropyl sulphide over p-toluene-sulphonic acid or potassium hydrogen sulphate under normal pressure. 2- methyl-1,4-hydroxythiane is thus obtained (boiling point: -46" C. at 18 mm.
Example Ill The 1 amino Z-ethyI-tetrahydro-1,4-thiazine-4,4-dioxide used as the starting compound in the foregoing synthesis may be obtained in a manner analogous to that described above in connection with Example II, (a)-(d), namely:
R is a member selected from the group consisting of hydrogen, lower alkyl, benzyl and phenyl.

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)

US323225A 1962-11-23 1963-11-13 Novel 5-nitro-furfurylidene-(2) derivatives and process for producing the same Expired - Lifetime US3262930A (en)

Applications Claiming Priority (1)

Application Number	Priority Date	Filing Date	Title
DEF38378A DE1170957B (de)	1962-11-23	1962-11-23	Verfahren zur Herstellung von 5-Nitro-furfuryliden-(2)-iminoderivaten

Publications (1)

Publication Number	Publication Date
US3262930A true US3262930A (en)	1966-07-26

Family

ID=7097312

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
US323225A Expired - Lifetime US3262930A (en)	1962-11-23	1963-11-13	Novel 5-nitro-furfurylidene-(2) derivatives and process for producing the same

Country Status (7)

Country	Link
US (1)	US3262930A (fr)
AT (1)	AT241450B (fr)
BR (1)	BR6354789D0 (fr)
CH (1)	CH426830A (fr)
DE (1)	DE1170957B (fr)
FR (1)	FR3257M (fr)
GB (1)	GB992166A (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US3488348A (en) *	1966-01-05	1970-01-06	Bayer Ag	5-nitro-furfurylidene-(2)-imino derivatives and their preparation
US3755308A (en) *	1970-04-25	1973-08-28	Bayer Ag	Nitrofurfurylideneamino derivative of octahydrobenzthiazine-1,-dioxide and process for its preparation
WO2010000398A1 (fr) *	2008-07-02	2010-01-07	Bayer Animal Health Gmbh	Nifurtimox pour le traitement de maladies provoquées par les trichomonadida
WO2010000399A1 (fr) *	2008-07-02	2010-01-07	Bayer Animal Health Gmbh	Utilisation du nifurtimox pour le traitement de la giardcciose
EP3750527A1 (fr)	2019-06-13	2020-12-16	Bayer AG	Formule de comprimé stable de nifurtimox et son procédé de production

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
DE1670840A1 (de) *	1967-03-31	1971-03-11	Bayer Ag	Verfahren zur Herstellung von Tetra-hydro-1,4-thiazin-1,1-dioxiden
US8406309B2 (en)	2005-10-21	2013-03-26	Qualcomm Incorporated	Video rate adaptation to reverse link conditions

Citations (1)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US3001992A (en) *		1961-09-26		S-niteo-z-fubftjewdene

1962
- 1962-11-23 DE DEF38378A patent/DE1170957B/de active Pending
1963
- 1963-11-11 CH CH1382263A patent/CH426830A/de unknown
- 1963-11-13 US US323225A patent/US3262930A/en not_active Expired - Lifetime
- 1963-11-13 AT AT907463A patent/AT241450B/de active
- 1963-11-19 GB GB45619/63A patent/GB992166A/en not_active Expired
- 1963-11-22 BR BR154789/63A patent/BR6354789D0/pt unknown
1964
- 1964-02-21 FR FR964742A patent/FR3257M/fr not_active Expired

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US3001992A (en) *		1961-09-26		S-niteo-z-fubftjewdene

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US3488348A (en) *	1966-01-05	1970-01-06	Bayer Ag	5-nitro-furfurylidene-(2)-imino derivatives and their preparation
US3755308A (en) *	1970-04-25	1973-08-28	Bayer Ag	Nitrofurfurylideneamino derivative of octahydrobenzthiazine-1,-dioxide and process for its preparation
WO2010000398A1 (fr) *	2008-07-02	2010-01-07	Bayer Animal Health Gmbh	Nifurtimox pour le traitement de maladies provoquées par les trichomonadida
WO2010000399A1 (fr) *	2008-07-02	2010-01-07	Bayer Animal Health Gmbh	Utilisation du nifurtimox pour le traitement de la giardcciose
US20110105388A1 (en) *	2008-07-02	2011-05-05	Bayer Animal Health Gmbh	Novel possibility of controlling giardiosis
US20110118176A1 (en) *	2008-07-02	2011-05-19	Bayer Animal Health Gmbh	Novel possibility of controlling diseases caused by trichomonadida
JP2011526264A (ja) *	2008-07-02	2011-10-06	バイエル・アニマル・ヘルス・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング	トリコモナス目に起因する疾患の処置のためのニフルチモックス
CN102083440B (zh) *	2008-07-02	2013-03-27	拜耳知识产权有限责任公司	硝呋替莫用于制备治疗由组织滴虫引起的疾病的药物的用途
US8440613B2 (en)	2008-07-02	2013-05-14	Bayer Intellectual Property Gmbh	Controlling diseases caused by trichomonadida
US8440612B2 (en)	2008-07-02	2013-05-14	Bayer Intellectual Property Gmbh	Controlling giardiosis
CN102083441B (zh) *	2008-07-02	2013-07-24	拜耳知识产权有限责任公司	硝呋替莫用于治疗贾第虫病的应用
AU2009266125B2 (en) *	2008-07-02	2015-06-04	Bayer Intellectual Property Gmbh	Use of nifurtimox for treating giardiasis
EP3750527A1 (fr)	2019-06-13	2020-12-16	Bayer AG	Formule de comprimé stable de nifurtimox et son procédé de production
WO2020249500A1 (fr)	2019-06-13	2020-12-17	Bayer Aktiengesellschaft	Formulation de comprimé stable de nifurtimox et son procédé de production

Also Published As

Publication number	Publication date
AT241450B (de)	1965-07-26
BR6354789D0 (pt)	1973-07-12
CH426830A (de)	1966-12-31
FR3257M (fr)	1965-04-20
GB992166A (en)	1965-05-19
DE1170957B (de)	1964-05-27

Publication	Publication Date	Title
CH616157A5 (fr)	1980-03-14
DE1695139B2 (de)	1976-11-04	1-(3-chlor-2-hydroxypropyl)-2- methyl-5-nitroimidazol
US3262930A (en)	1966-07-26	Novel 5-nitro-furfurylidene-(2) derivatives and process for producing the same
US3769295A (en)	1973-10-30	Nitrofuryl derivatives of 5-substituted isoxazolines
US3338917A (en)	1967-08-29	Diimidazolinylcarbanilide
US3334126A (en)	1967-08-01	Aryl n-methyl substituted thionocarbamates
US3075974A (en)	1963-01-29	3-(2-(4-morpholino) ethyl)-1-(5-nitrofurfurylidenamino) hydantoin and acid addition salts thereof
US2920074A (en)	1960-01-05	1-(5-nitrofurfurylideneamino)-2-imidazolidinethione
CA1069125A (fr)	1980-01-01	La 4-imino-1,3-diazabicyclo-(3.1.0) hexan-2-one
GB981046A (en)	1965-01-20	Hexahydro-4ah-8,9c-iminoethano phenanthro-[4,5-b,c,d]-furan derivatives
US3141889A (en)	1964-07-21	1-(2-oxo-3-oxazolidinyl)-2-thiourea
US2460139A (en)	1949-01-25	Alkamine esters of 2-chloro-4-amino benzoic acid
US3222398A (en)	1965-12-07	Heptyloxyphenyl biguanide compounds
US2606903A (en)	1952-08-12	Ascorbic acid addition compound of sulfathiazole
DE1670657C3 (de)	1975-01-23	4- eckige Klammer auf 5-NHrofurfuryliden-(2')-lmino eckige Klammer zu -tetrahydro-M-thlazln-i.i-dioxld-Derhrate und Verfahren zu Ihrer Herstellung
US3146232A (en)	1964-08-25	5-(5-nitro-2-furyl-mono- and di-vinylene)-1, 3, 4-oxadiazoline-2-one and process
US2847416A (en)	1958-08-12	Nu-[1-(5-nitro-2-furyl) ethylidene]-3-amino-2-oxazolidone
US3076805A (en)	1963-02-05	New 1-(hydroxy(lower) alkyl)-3-(5-nitrofurfurylideneamino)-2-imidazolidinethiones
US3678040A (en)	1972-07-18	Process for the preparation of hydroxybenzene sulfonates of morpholinomethyl aminooxazolidones
US3538225A (en)	1970-11-03	Control of animal disease using certain 2,3-dihydro-5-carboxamido - 6-methyl-1,4-oxathins
US2787574A (en)	1957-04-02	Substituted phenyl urea compositions for treating coccidiosis
US3151110A (en)	1964-09-29	Alcoholates of 3-amino-6-substituted-1, 2, 4-triazine compounds
US2628233A (en)	1953-02-10	Substituted and unsubstituted barbiturates and thiobarbiturates of 1, 2, 3-trisubstituted pyrazolones and processes of producing such compositions
US3621013A (en)	1971-11-16	Formamidine compounds of diphenyl-sulfone
US3981915A (en)	1976-09-21	Amides of 1-aminocyclopentane carboxylic acid