DE1670017A1 - Thiazine derivatives and a process for their preparation - Google Patents

Description

MÖNCHEN 23 SIEGESSTRASSE 26 TELEFON 345067 TELEGRAM ADDRESS: INVENT / MONCHEN

U.S .: D 065 22 * Dea. 196?

SS 1929 Bu / j / hh

Allen and Henburya, linsitsd London, UK

Thiazine derivatives and a process for their preparation

Priority: i> 3. December 1966 / Great Britain -ür.t 57 65O / 6ß

The JSrfindung relates to new thiazine derivatives and their salts biological effectiveness, such as analgesic and anti-inflammatory Effect, and a method for producing it.

The thiazine derivatives of the invention have the general Formulas

(X) (II)

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in which η has the value 3 or 4, R ^ is a hydrogen atom or one or more alkyl radical (s) and Bg and B-, which can be the same or different, mean a straight-chain or branched alkyl radical with 1-6 carbon atoms or Bg and B- together denote an alkylene group (CHg) ₀₁ , where m has the value 4 or 5, and the ring thus formed can be substituted by one or more alkylreet (θ), R. and B,., Which can be identical or different , a hydrogen atom or a straight-chain or branched alkyl radical with 1-6 carbon atoms or an aryl, acyl, aroyl or alkoxyoarbonyl radical or R ^ and Re together with the adjacent nitrogen atom form a heterocyclic ring which optionally contains further heteroatoms, Bg and R ", which can be the same or different, denote a straight-chain or branched alkyl radical with 1-6 carbon atoms, or Rg and R" together denote an alkylene group {Q&J) , where ρ is the value 2 or 3 h at. The invention also relates to salts of thiazine derivatives of the formulas X and II.

Preferred thiamine derivatives are those whose production is described in the examples.

It has been found that the thiamine derivatives according to the invention or their physiologically suitable salts have a favorable biological activity, such as an anaesthetic or anti-inflammatory effect. These connections can be used for used for therapeutic purposes in human or veterinary medicine.

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For example, the thiazine derivative III

ί Α

IF-

ale in mice protection from the deterioration caused by ultraviolet radiation erythema about as effective (Ede ₀ about 10 mg / kg) such as indomethacin (SD _Q 7 _t? rag / kg) · Ale antagonist in the inflammation involved in the injection of Garageenin in occurs in the hindfoot of the rat, the thiazine derivative III has a value of 27.5 mg / kg (indomethacin has an E value of 9.6 agAg). The thiazine derivative III, however, has clear advantages over indomethacin in terms of avoidance A build-up of oil in the gastrointestinal tract and ee also counteract the retention of salt and water in the body.

The invention also relates to drugs that are effective Component of the thiazide derivatives according to the invention or their contain physiologically suitable salts. Serious drugs can common carrier substances or ezol patients and, if necessary, contain other additives and, if necessary, additional medical active ingredients

The drugs can, for example, in fora faster and liquid preparations for oral administration, suppositories and injections. Oral administration takes place on two in the form of conventionally prepared Tablets that may be coated. Injection fluids can be used in conjunction with physiologically suitable

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Notes carrier substances and other means as solutions, Suepen-Bionen or as dry products, which are then used before use to be dissolved again, to be produced. The effective daily dose of active ingredient can be used as required vary, but is generally based on neon age, weight * and condition of the patient between 50 and 5C0 ag

The thiamine derivatives according to the invention can by condensation a cycloalkanone or an alkylldenoyoloalkanone with! thiourea or a corresponding thlourea derivative.

or

Thus, the Thiazlnderivate of formula Z by condensation of cycloalkanones or Alkylidenoyoloalkanons with thiourea or a monoeubetituierten or I ₉ I-Aisubstituierten thiourea can be prepared, for example.

.GS.HH

/ "" (CH ₉ Jn + 1

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2'n

if R4 and / or Re in the thiourea is an acyl, aroyl or alkoxyoarbonyl radical, then during the condensation, as a result of the strongly acidic conditions, these best thiazine derivatives of the formula I in which R ^ and / or H _{5 are} an aoyl , Aroyl or alkoxyearbonyl radical, but can be prepared in a manner known per se from the corresponding compounds in which R. and / or Rc denote a water etoffatoa, for example by reaction with an aoyl or aroyl halide or with an alkyl chloramaisenate.

In the above formulas, R ₁ , H ₂ , R ^, R ^, R_ and η have the meaning already explained. The value η + 1 in the carbocyclic ring spirooyolisohen compound is equal to m, as nlert above defl.

The thiamine derivatives of the formula ZZ can by condensation a; Cycloalkanone or Cysloalkylideneyoloalkanons with 1,3-disubletitulertcm Thiourea.

R,

Xh the formulas have E ,, Rc, R- and η which have already been explained Meaning.

The condensation can be carried out in the presence of an acidic catalyst, such as concentrated hydrochloric acid or 60% sulfuric acid will. The condensation can be in the absence or in

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Contemporary elnee £ ttsungeslttels ₉ as Xthanol, done · Dae Beaktionagenieoh can be genalten several hours BttokfluS or bie at room temperature stubborn completion of the condensation are grerOhrt.

The following examples explain the preparation of thiamine derivatives *

Example 1

2-aaino-4,5 _f 6,7-t etrahydro-epiro ^ oyolopenta (d) 3, l-this »in-4,1 * <»

oyolopentanjealeät

84 ml of cyclopentanone and 7.4 g of thiourea are mixed with 20% sentrierter Sa & a & ure 20 hours erhitst to 80 ⁰ C "Paa

Oemieoh is diluted with 200 al faeaer and 2 al "it each 200 al Xther extracted · You w & aarige Ihaae is alkelieoh sewn

and 3 "al with 150 al Xther extracted" Duron evaporation dee ethereal extract tea is given «to an oil, mn» d · «am to dea

Mkriatalliaieren au · lthylaoetat 10 g kriatitUia ·· Äaleat eit

The other child point of 166 ⁰ C wins.

411y

300 ml of cyolohexanone and 92 g of 1,1-Dlüi ihylthioharnetoff are ' heated with 100 ml of concentrating saleelure for 1.3 hours under RüokfluS. Bat öemieoh is cooled and ait ether extract ^ · The wlaarige Phaee is alkalinoht and 3aal ait ever 300 ml Xther extracted. The extracts are washed, dried and evaporated. The oily residue, which on cooling

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becomes solid, is crystallized from 80- ^ igeci aqueous Xthanol. 82 g of thiasin are obtained from a Sehmel point γοη 74-75 ° 0. Its solution τοη 592 g of the base in 1200 ου. Bensol is treated with an equivalent of a 2-normal Sthanollsohen hydrochloric acid and then the solvents are removed. One g de · Hydrochloride Duron recrystallization ous one Bensol / Xsopropylaoetat-Oemleoh receives 612.5 with a melting point of 182 ⁰ O.

Example 3

? -Aottemido-5,6,718-tetrahyärc-ipiro ^ f4H) - ^, l-benc «5thiaein-4,1 '- ( oyolohexane ?.

5 «5 B 2-Amino» 5 * 6 ₉ 7 _t 8-tetrah7dro-epl7o ^ r4H) -5 »l« beneothlasln- 4 »l * -oyelohexmn ^ hydrochloride in 50 ml of chloroform, of 6 ml contains fri & thylamine, 1.95 ml of aoetylochloride ^{are added at O 0 O} treated. The solution is kept for 24 hours at a Zimatrtemperator evaporated and the residue treated with 7aeeer and Xther.

The extracts from them are evaporated and obtained

after recrystallization of the Bttokatandee aua xthylaoetat 4.6 g dee Ihiasins with a Sehmeispunkt τοη 174 ⁰ C.

4 -

The fhiasin rates listed in Table I are prepared in the same manner as in the examples above represented derivatives obtained

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example R. position S ₄ - H 250-251 * 4th R. R. methyl 165 5 H - Π Xthyl 95 6th Π - Π ββο-butyl 67 7 .. II - Π Oarboxyethyl 171-172 * 8th R. - R. Phenyl 180 * 9- H - R. Acetyl 66-67 10 H - Xthyl Bensoyl 144-145 11th H - R. Propyl 82-84 12th H - R. Xthyl 87-89 13th H - Xthyl OHg) ₂ - 177-181 * 14th B. - - (CH ^) ₂ OC 67-70 15th R. - - (CHg) ₅ - H 180..185 * 16 methyl 4 », 6 H methyl 150 17th methyl 4 ·, 6 H Xthyl 103-104 18th methyl 4S6 H methyl 104 19th methyl 4 ', 6 methyl R. 150-151 20th methyl V , 7 R. Xthyl 217-219 * 21 t he t.-BuIyH ¹ , 6 H

a ■ Hydfoohlorld

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Example 22

2-Dimethylamino-5 »6» 7 »8-tetrahydro-4,4« 7-trimethyl- (4H) 3,1-benzothiazine.

Am mixture of 15 ml of 3-Δ ^ ⁸ '-Mentencn, 4 g of 1,1-dimethylthiourea and 100 ml of saturated ethanolic hydrochloric acid is left to stand for 24 hours at 30 ⁰ C. The solvent is removed and the residue is taken up in 50 ml of 2N hydrochloric acid and extracted with ether. The aqueous phase is made alkaline (Pjj 12) and extracted 3 times with jev, eils 100 ml of ether. These extracts are washed, dried and evaporated. The yellow oil obtained is recrystallized from Äthylaoetat and there is obtained the maleate with a melting point of 130 ° C.

The following connections are made in a corresponding manner.

Example 23

2-Amino-5 »6 , 7,8-tetrahydro-4,4,7-trimethyl (4H) -3, 1-benzothiaaine.

M.p. 102 ^° C.

Example 24

2-Xthylamino ~ 5 , β * 7 »8-tetrahydrc-4,4,7-trimethyl-C4H) -3, 1-benao thiazine hydrochloride. Mp. 92 - 93 ⁰ O

example 25th

2-Amino-4- (1 ^ ethylpropyl) -5.6 ₁ 7,8-tetrahydro- (4H) -3,1-benao thiaein hydrochloride. Mp. 136 ⁰ C _t

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-XO-

Example 26

2,3,7,8,9,10-hexahydro-epiro / (lH, 6H) pyrimido £ L, 2-a / -5,1-benzothiazln-6,1 ^f -cyclohexanT.

49 ml of cyclohexanone and 5.8 g of tetrahydropyrimidine-2- (1H) -thioa are heated for 2 hours under BüokfluS with 10 ml of concentrated hydrochloric acid. The mixture is cooled, diluted with 40 ml of water and extracted with Xther. The aqueous phase is made alkaline and extracted 3 times with 100 ml of Xther each time. An oil is obtained by evaporation of the ethereal extract, from which, after recrystallization from cyclohexane, 10 g of the thiazine with a melting point of 110 ⁰ O is obtained. The corresponding hydrochloride has a melting point of 235 ^° C.

The following connections are made in a corresponding manner

Example 27

1,2,6,7,8,9-Hexahydr o-spir oj { 5H) -imidezo ^ l, 2-a / 3,1-benzo-

thiazine-5, l ^f -cyolohexane 7. Tp. 115 ⁰ C.

Example 28

1 -Xthyl-2-ethylimino-1,2,5,6,7,8-hexhydro-spiro / (4H) -3,1- benzothiazine-4, l * -cyclohexane / hydrochloride. Pp. 173-175 ⁰ C.

Example 29

1,2,5,6,7,8-Hexahydr o-l-me thy 1-2-iie tnylimino-epir o / (4H) -3,1-

benzothiazine-4, l * -oyolohexane / hydroohXorid. Tp. 176 - 179 ⁰ C.

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Example 30 Manufacture of τοη tablets.

12.5 kg 2-Dinethylamino-5 »6» 7,8 ~ tetrahydro-8piro / (4H) -3 _t lbeniothiaEin «4 ₉ l ** oyolohexane / and 5 kg calcium sulfate become τβ rad real, then enough 1- A fl uid aqueous sodium oarboxymethyloellulose solution is added and mixed until a sticky mass is formed. “The hot cash register is granulated by letting it pass through a liohten width of 0.49 em and then adding the granules 50 ⁰ O trooknet · Haoh dem frooknen one has to pass the dried granulate through a 8isb with a liohten Hasoheuwsite clay 0.385 bisi and isoht it with 3 »75 kg corn starch and 125 g magnesium stearate. Bas old lubricated granules are rerpressed with the help of a suitable tableting machine su tablets. The tablets have a weight of about 430 mg and contain 250 mg of 2-di- ■ ethylamdno «» 5 »6 · 7 · β-tetrahydro-spiro / (4H)« 3,1-bensothiasln-411

Example production of τοη capsules.

1 kg 2-Dim "thylemino-5f6,7,8-tttrahydro-epiro / (4H) -3, l-bensothie" in-4, l ^t "oyolohexan7wird with so riel mikrokrlstslliner cellulose Termischt that the Oelatinekapseln filled dieaem PulTergemisoh Mr. 3 100 mg 2-bimethylamino-5,6 _f 7 ₉ 8-tetrahydro-epiro ^ T4H) -3,1-benso thiasin-4,1 * -oyolohexane / contain ·

Instead of the 2-bimethyl used in Examples 30 and 31 • mino-5,6> 7 »8-tetrahydro-spiro ^ 4H) -3, l-bensothiaein-4,1 * -oyolo-

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hexane , the thiazine derivatives listed in Examples 1 to 29 can also be used.

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Claims (1)

1670ÜT / - Claims 1 * Thiasin derivatives of the general formulas •• to "· (D (II) and their salts, in which η has the value 3 or 4 and R _{1 is} a hydrogen atom or one or more alkyl radical (s), Rg and R-, which can be the same or different, mean a straight-chain or branched alkyl radical having 1-6 carbon atoms or R ₂ and R * together represent an alkylene group (CH ₂ ) _m , where m has the value 4 or 5, and the ring thus formed can be substituted by one or more alkyl radical (s), R ^, and Re, which are the same or can be different, a hydrogen atom or a straight-chain or branched alkyl radical with 1-6 carbon atoms or an aryl, acyl, aroyl or alkoxyoarbonyl radical, or B, and R, - together with the adjacent nitrogen atom form a ring, which optionally also further Contains heteroatoms, Rg and R ", which can be the same or different, mean a straight-chain or branched alkyl radical with 1-6 carbon atoms or Rg and R" together mean an alkylene group (CH ₂ ) - "; obei ρ the value 2 or he has 3 2 · 2-Dimethylamino-5,6, T, 8 ~ tetrahydro-.spiro / (4H) -3, l-benzo- 009833/1942 thiazine-4,1 * - »eyolohexao /. 3. 5,6,7,8-Τβ trahyär 0-4 '»6-dimethyl-2-methylamino-ipiro2 (4H) 3, l-ben2othiazine-4, l'-cyolohexane /. 4. 2-Amlno-4 (1-ethylpropyl) -5,6,7,8-tetraliydro- (4H) -3,1ben-thlazine hydrochloride. 5. 2,3,7,8,9,10-Heiahydro-spiro ^ (IH, 6H) -pyrimido / l, 2-3, l-benzothiazine-6,1 * 6 x 5,6,7,8 ~ tetrahydro-2-piperidin-epiro ^ (4H) -3,1-benzothiaein 4,1 '-oyoloheian /. 7 · 2-Amlno-5,6,7,8-tβtrahydro-epiro ^., 3-fcen8othiasln-4,1 * - oyolohexai ^ hydrochloride " 8 · 2-N-methylamino-5,6,7,8-te trahydro-epiro ^, 3-benzo thiaein 4, l'-oyolohexane /. 9 · 2-H-Xttaylamino-5,6,7,8-tetrahydro-epirOj / i ₉ 5-bezusothiasln-4 * 1'-cyolohexane /. 10. 2-lfthla »in-4, l'-cyclohexay 11 • a-B-Carboayethylanino-S, 6,7,8-tetrahydro-apiro ^ L, 3-beaeo thiazine-4,1'-eyolohexane / hydrochloride 009833 / 19A2 12 "2-K-Phenylamino-.5 _f 6,7,8-'tetrahy" ro-ßpiro ₁ öL, 3-i> eaeothiael "- 4,1'-cyclohexaiyhydreohloriJ · 13. 2- (if-Xthyl-K-aoetyl) aiaino-5,6,7 »8-tetrahydro-epiro / 1,3-benso thiazine-4,1 -cycloheacan / 14 · 2-N-BenBoylaaino-5 »6 ♦ 7,8-tetrahydro-apiro ^ L, 3-beiusothiasln-4» 1 * 15 «2-N-PropylaBino-5,6,71θ-tetrahydro-epiro ^ l, 3-ttneothiaBin- 4,1'-oyolohexay. ' 16 ·? * H, K-diethyltäino-5,6,7 »8-tetrahydro-epiro ^ _v 3-ΐ> · ωοthiaein-4, V -oy olohexane /. 17 · 2 1 4 * -Moppholino-5,6 »7» β-tttrahydro-eplro ^, 3-tHinB0thia »in 4,1'-oyolohexaB / hydrochloride 18 x 2.1 "-piperidino-5,6,7,8-tttrahydro-epiro ^ L, 3-benEothianin 4 »1'-cyolohexane 7. 19 · 2-ABino-5, £, 7 _t 8-tetrahydro-6,4'-diaethyl ~ epiro / i, 3-thiaEin-4,1 * -cyclohexan ^ hydrochloride. 20. 2-H-lUthyleeino-5,6,7,8-bniothlasin-4,1 * -oyolohexane /. 21. 2-W-JUhyl "" in © -5,6,7,8-tetrahydro-6,4 * bensothiaein-4,1 * -cyclohexane. 00983371942 22. 2-N, N-Dimethylamino ~ 5 , 6 »7 , 8-tetrahydro-6,4'-dimethyl-epiro- , 3-benzothiazine-4,1 '-cycloherazy. 23. 2-Amino-5 , 6,7 , 8-tetrahydro-7,3 ^f -dimethyl-epiro ^ L, 3 ~ ben »othiaBin-4,1'-cyolohexane ^. 24. 2-N-Xthylamino-5 _f 6 , 7 »8-tetrahydro-6,4 * -di-tert-butyl-epiro · Jl , 3-beneothiaein-4,1'-cyolohexane / hydrochloride. 25 · Process for the preparation of the thiamine derivatives τοη Anipruoh 1 - 24 _f by using a cycloalkanone of the general formula ♦ 1 in which η has the value 3 or 4 and R ₁ denotes a Waeeeretoffatoa or one or more alkylreet (s) or · denotes »or an alkali metal diolalkanone of the general formula ♦ 1. in which η and R ^ have the above meaning, or a cycloalkanone the general formula \ ^ " ^R 2 C " 009833/1942 in which η and R _{1 have} the above meanings and R ₂ and R *, which can be the same or different, mean a straight-chain or branched alkyl radical having 1 to 6 carbon atoms, or R ^ and R * together represent an alkylene group (CH ₂ ) J _n mean and the ring thus formed can be substituted by one or more alkyl radical (s), a) with thiourea or a monosubstituted or 1,1-disubstituted one Thiourea derivative of the general formula ₀ <T
«^ R
S 5 in the R ^ and R ^, which can be the same or different, a Hydrogen atom or a straight or branched alkyl chain with 1-6 carbon atoms or an aryl, acyl, aroyl or Alkoxycarbonylreat or R ^ and Rc together with the adjacent nitrogen atom form a ring, which optionally contains further heteroatoms, to thiazine derivatives of general formula in which n, R ^, R ₂ > R3 »R4 and Re have the above meaning, converts, or b) with a 1,5-disubstituted thiourea derivative of general formula RgHK - C - NHR ₇ S 009833/1942 in which Rg and R ₇ , which can be the same or different, denote a straight-chain or branched alkyl radical with 1-6 carbon atoms or Rg and B «together denote an alkylene group (CHg), where ρ has the value 2 or 3, to xhiazine derivatives general formula h I " 'in which n, B ^, R «, H«, Rg and R »have the above meaning, implements 26o pharmaceuticals, characterized in that it contains a thiazine derivative YQn claims 1-24 or a physiologically suitable salt of such a derivative as an active ingredient » 009833/1942