DE2241140A1 - THIAZINE DERIVATIVES - Google Patents

Description

G. Ivan the Warfh? Aug 2, 1972

Di. fruu * Lederer

RAN 4002 /16.x

F. HofFmann-La Roche & Co. Aktiengesellschaft, Basel / Switzerland

Thiamine derivatives

The present invention relates to new thiazine derivatives, and also spirothiazine compounds of the formula

wherein R, hydrogen, lower alkyl, lower alkenyl, aryl-nicder-alkyl, aryl, lower alkanoyl or benzoyl; R _p lower alkyl, lower alkenyl, aryl, aryl ~ lower-alkyl, or a group

As / 7/20/72

3098097 1 183

of the formula -t'-R / »where R. is lower alkyl,

Nn ph thy]., Cycloalkyl, smbstitiiiiirton gynln-alkyl, aryl-lower-alkyl, styryl or one of the groups - (CHg) -R, - and HH-R _ß where Rj- means lower alkoxy or lower alkoxycarbonyl, Rg lower alkyl or phenyl and m represents a number from 1 to 6; where furthermore R, and R _? together a group of one of the formulas

ο ο

odor J

wherein Y is a lower alkylene group having 1 to 10 carbon atoms or an o-arylene group is; R_ water, lower alkyl, phenyl, 3,5-di- (lower alkyl) -iooxazol-4-yl-ethyl, . 4,4-lower alkylenedioxy or arylenedioxy-1-pentyl or 3-cyanopropyl and η a Zalil means from 1 to 3,

and the tautomers, enantiomers and acid addition salts here

If R, or R _? If hydrogen means, the geu der Foi'iilöi I IiI νβ! Γαθ1ι1θΟ.6ίϊόη "fc &utOuiri" ßri 1 ^: 0ViTiCiI

occur, depending on the type of substituent R- or Rp » depending on whether the compound is in the crystalline state or in solution, depending on the type of solvent,

309809/1183

^:} BADORfGINAL

. 2241143

dor temperature and the like. A number of possible tautomorous forms of compounds where R _{1 is} hydrogen and R _{0 is} the

group

are shown in the form below

Schena reproduced. In the description that follows but, in order to avoid errors, all "connections of formula I in the tautomeric form i and named accordingly (i.e. with an endocyclic double bond and al "non-enolized amide).

iii

Under the expression ^l! Alky! Group "is to be understood in the following as a straight-chain or branched saturated hydrocarbon group with up to 20 carbon atoms, for example methyl, ethyl, hexyl, isopropyl, tert-butyl, decyl, etc. The expression" cycloalkyl group "relates to saturated hydrocarbon groups with at least one carbocyclic ring which contains 5 to 8 carbon atoms * Examples of such cycloalkylg - ;. ppe: _f -i are cyclopropyl, cyclopentyl, cyclohexyl, cyclooctyl, 1-adamantyl and the like. The term "alkenyl group" refers to straight-chain or the like - twisted, olefinically unsaturated hydrocarbons

3 0 9 8 0 9/1183

2241U0

groups with up to 20 carbon atoms, such as Vinyl, Iüopx-open, yl, 2-butenyl, 2-hexenyl, and the like. Der The term "aryl" refers to monocyclic or bicyclic, aromatically unsaturated hydrocarbon groups, which is a free valence emanating from the aromatic ring exhibit. Examples of such aryl groups are phenyl, 2-naphthyl, p-tolyl, p ~ fluorophenyl, m-methoxyphenyl and the like. The term "alkoxy group" refers to radicals formed by removing the hydrogen atom from the hydroxy group of a straight-chain or branched alkanol with up to 20 Carbon atoms. Examples of such alkoxy groups are methoxy, ethoxy, propoxy, butoxy and the like. The term "alkanoyl" refers to radicals formed by removing the hydroxy group from the carboxy group of a Alkanecarboxylic acid / up to 20 carbon atoms are formed. Examples of such alkanoyl groups are formyl, acetyl, Propionyl, pivaloyl, hexanoyl and the like. The term "alkylene group" refers to straight chain, saturated hydrocarbon groups of up to 20 carbon atoms, which have a free valence at each terminal carbon atom. The term "ortho-arylene group" refers to a group that contains an aromatic ring, which has two free valences that emanate from neighboring carbon atoms of the aromatic ring. Of the The term "lower" refers to groups which contain a carbon skeleton which is up to and including 8 carbon has a tome. Examples of aryl-lower-alkyl groups are benzyl, 2-phenylethyl, 1-phenylethyl, p-methylbenzyl, p-nitrobenesyl and the like. The term "substituted" refers to in connection with a phenyl group, to a with phenyl ring substituted for one or more of the following: lower alkyl, trifluoromethyl, phenyl, halogen (i.e. Fluorine, chlorine, bromine or iodine), nitro, cyano, lower alkoxy, hydroxy, amino, lower alkylamino or di (lower alkyl) anino

309009/1183

_ C

The term "hetoroaryl group" refers to monocyclic ones or bicyclic G groups which have an aromatic ring with at least one having a heteroatom »Examples of such Hcteroarylgruppen are puryl, thienyl, pyridyl, Indolyl, pyrrolyl, pyrazinyl, pyrimldinyl, quinolyl, isoxazolyl and the like. Dor expression "substituted cycloalkyl group" refers to cycloalky! groups, which with one or more lower alkyl groups or phenyl groups are substituted.

Preferred compounds of the formula I. are those in which R-, hydrogen and R ₀ denote a group of the formula U _Ώ ,

viorin is R, phenyl, substituted phenyl or styryl, or those in which R ,. and R ₂ together represent a phthaloyl group;

where?.? in η represents the number 2 and R “represents hydrogen. Particularly

compounds in which R. is a phenyl group are preferred, which is monosubstituted in the m- or p-position.

The compounds of formula I can be prepared from the corresponding amines of formula

II

where R ™ and η have the above meaning,

by replacing one or both hydrogen atoms of the amino group duroh a substituent R- and / or Rp produced will. For example, compounds of the formula

3QS809 / 118 3

22A1U0

HO

Yes

wherein R 'is lower alkyl, phenyl, substituted phenyl, cycloalkyl, substituted cycloalkyl, naphthyl, heteroaryl, aryl-lower-alkyl, styryl or the group - (CH ₂ ) -R ₁ -, in which R ₁ . represents lower alkoxy or lower alkoxycarbonyl, and R_, m and η have the above meaning, are prepared by the amine of the formula IT. treated with an acylating agent in the presence of a baee. Suitable acylating agents are, for example, acyl halides, for example acetyl chloride, benzoyl chloride, p-fluorobenzoyl chloride and the like; Acyl anhydrides such as acetic anhydride, propionic anhydride and the like; Acylimidazoles; Acyl esters, for example tosylates, mesylates, p-nitrobenzoates and the like. Preferred acylating agents are acyl halides and acyl imidazoles. Suitable bases are for example alkali metal hydroxides, for example Natriumhj ^r droxyd and organic amines such as pyridine, triethylamine and the like. Preferred bases are chops! organic amines, especially pyridine. If an acylimidazole is used as the acylating agent, no additional amine is required. The reaction can be carried out in any organic inert solvent, for example in hydrocarbons, for example benzene, toluene, hexane and the like; in ethers, for example diethyl ether, tetrahydrofuran and the like; or in a ÜeberBchuaa of the amine used for carrying out the reaction. The liquidation reaction can take place within a wide temperature range

309809/1183

from about -20 ° to the boiling point of the Reaktdonsgosiificb.es carried out -.rerclen. In general, the Acylicrungs ~ roaktion vorisu / vnvreise is between 20 \ ma 50 ° - in particular at room temperature. Compounds of the formula Ib

Ib

"viorin R ₇ , R ^ and η have the above meaning can be obtained from compounds of the formula II by reaction with a lower alkyl isocyanate, for example methyl isocyanate; or with phenyl isocyanate in an inert organic solvent. Suitable solvents are, for example, hydrocarbons, for example benzene, Toluene, hexane and the like; chlorinated hydrocarbons, e.g. methylene chloride j chloroform and the like; ethers, e.g. diethyl ether, tetrahydrofuran, dioxane and the like; esters, e.g. ethyl acetate; amides, e.g. dimethylformamide and the like. The temperature is not critical and can be between about 0 and about 100 ⁰ C. Am preferred temperature range is between about 20 ° and about 50 ⁰ C, and carrying out the reaction is preferably carried out at room temperature.

Compounds of the formula Ia can be prepared by reaction with an alkylating agent or with an acylating agent alkylated in the presence of a strong base or

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22A1U0

be acylated. Examples of suitable alkylation oils üi.iid lower alkyl halides; iri ^ dcr alkenyl- halogen.idc or aryl-ni.or -all:; ylha.lr! ^ ertiary :, for example Methyl iodide, ethyl iodide, bentryl chloride and the like; lower alkylsulfonylooter, lower alkenylsulfonyl ester or aryl-lower-alkylsulfonyl esters, for example tosylates or mesylates. Suitable acylionin agents are the same

0 as described above for the introduction of the remainder U _n . Alkali metal hydrides, for example sodium hydride; Alkali metalomides, for example sodium amide; Alkali metal alkoxides, for example sodium ethoxide; and the like. Used.

Suitable solvents for carrying out the reaction are hydrocarbons, for example benzene, toluene and the like; Ethers, for example tetrahydrofuran, moxane and the like; Amides such as dimethylformamide, dimethylacetamide and the like; Sulphoxides, such as dimethyl sulfoxide and the like. The reaction can be carried out in a temperature range between about -2O ⁰ C and 10O ⁰ C. A preferred temperature range is between about 0 ° and about 50 ⁰ C. The carrying out the reaction at room temperature is particularly preferred.

The above reaction gives compounds of the formula Ic

Ic

wherein R 'is lower alkyl, lower alkenyl, AryJ-ηί e'ler-alkyl, lower alk-moyl or Bonrsoyl 309809/1183

BATH ORIGINAL

2241 HO

Iind Rz> R * λ 'üftä- ⁿ have the above meaning. Compounds of the formula

Id

v ^T orin R ".. lower alkyl, lower alkenyl, aryl, or aryl-lower-alkyl and R ~ and η have the above meanings,

can be obtained by either removing the acyl group from the nitrogen atom of the corresponding prebond of the formula Ic or, if R ¹ ! Aryl means, according to the process described below for the preparation of the compounds of the formula Ie.

A compound is preferably used for the antacylation of the formula Ic is used, which has an easily removable acyl group on the nitrogen, for example the formyl group or the acetyl group. The acyl group can be removed, for example, by treatment with an aqueous Acid or an aqueous base. Suitable acids are kineral acids, e.g. hydrochloric acid, sulfuric acid and the like; organic Sulfonic acids, for example p-toluenesulfonic acid and the like. Suitable bases are alkali metal hydroxides, e.g. ITatrlwiihydroxyd or potassium hydroxide. The reaction can be in the aqueous acid or the aqueous base with or without Use of another solvent can be carried out. Suitable further solvents are, for example, alcohols, e.g. methanol or ethanol; miscible organic ethers,

30 9 8 09/1183

BATH ORIGINAL

2241HO

for example, tetrahydrofuran, dioxane and the like. The reaction temperature may »" .zicchcn about room temperature and the boiling point of Reaktionsgemischea are "Preferably vird a temperature in the range of about 50 to 120 ⁰ O used.

The compounds of formula II can be obtained by means of a new process which involves condensation of a hydroxy vinyl ketone of the formula

OH

Wn

O <? ^H 2> n

R,

or its addition product of the formula

IHa

(CH ₀ )

2> n

where X is a group halogen. Chlorine, bromine or iodine or a group of the formula N ^ wherein R ,, and R "are independent of one another lower alkyl or üuea-aueii lower Alkylene with 4 to 6 carbon atoms

H ₁

HIb

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- 3 "L -

22A1HÜ

means and R_ and η have the above meaning

inspects with Tliioharnnboff "" KicrfiJr suitable Looungßmittel ■ ^ are lower Alj mearbonsäiiren, beirapielmr.eisG acetic acid;.. and aprotischo organic solvent, at cpißlsweise acetonitrile, dimethylformamide _f tetrahydrofuran and the like The reaction may be in a temperature range below swischen Räumtempc5ro.tür and the boiling point of the reaction mixture: "carried out".; however, a reaction temperature of about room temperature is preferably used. According to a preferred vasführurigfjforiu, in the future, X may be group 1 \ L

^X means R, the condensation reaction is carried out using a lower alkali carboxylic acid as a solvent. The use of acetic acid is particularly preferred here. The thiazine of the formula II obtained can be isolated either in the form of the free base or in the form of an acid addition salt Can be separated, either giving the corresponding free bases or corresponding acid addition salts. The mixture can, however, also be converted into a mixture of derivatives of the formula I, which is then separated "Compounds of the formula IHa and IHb, in which η represents the number 2, and R" is hydrogen, lower alkyl, 3,5-di (lower alkyl) isoxazol- • 'i-yl-ethyl, 4 »4-lower alkylenedioxy or arylenediozy-1-pentyl are known compounds. The compounds in which IU denotes phenyl are prepared in an analogous manner to those in which R ₇ denotes lower alkyl, starting from S -phenyl- & alerolactone. The compounds of the formula IHa and HJb, in which R ₀ , 3-cyanopropyl and η denotes the number 2, küijj'im {', OiOfisS Ci GiJi f Ol.fi CO id 6Γ'. Iv6 & kiionSSCll6ij.3, hC-iY-i ^ ijtCiilt

Ground:

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BAD ORfGINAL

NC (clip), C.

(CH) - CN.

(a)

22-41 HO

L · C-

C OH

(b) YesI

NC -CH

(d)

Vinylierungsmittcl

H'

(M ₂

CH

CH

2 Ό

(I ₁ )

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2241 HO

In the first step of the above reaction sequence, the known 2,2-di (5 ~ oyanopropyl) -l, 3-dioxolane (a) is selectively hydrolyzed using a dilute aqueous acid in the presence of a water-miscible organic solvent, whereby 5- Oxoazeleonitrile (b) is obtained. This hydrolysis is carried out in such a way that the labile nitrile group is retained. For this purpose, dilute aqueous mineral acids, for example hydrochloric acid or dilute aqueous organic acids, for example acetic acid, can be used. The use of dilute hydrochloric acid is preferred. Water-miscible organic solvents can be ketones, for example acetone, ethers, for example tetrahydrofuran, and organic acids, for example acetic acid. The preferred solvent is acetone. The reaction may be carried out at temperatures between about -20 ° C and +50 ^0. The preferred temperature range is between 10 ° and 30 ⁰ C.

The reduction of the carbonyl group in compound b is carried out by means of a metal hydride, for example by means of sodium borohydride, using a non-ketonic organic solvent, for example a lower alkanol, for example methanol} a water-miscible ether, for example tetrahydrofuran, or the like. The preferred solvent is aqueous methanol. Bin more expedient temperature range for this reaction is between 10 ° and 30 ⁰ C.

The symmetrical di-cyano alcohol thus obtained (c) is then subjected to selective acid hydrolysis, whereby 8-cyano-5 ~ hydroxy ~ octanecarboxylic acid lactone (d) receives. To carry out this reaction it is necessary to have one equivalent of water and one equivalent of a strong one Acid, for example a mineral acid or an organic sulfonic acid, e.g. p-toluenesulfonic acid to be used. These Reaction can take place in a hydrocarbon solvent., Both

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-U-

spielrjVGir, G toluene, at temperatures between 20 and 1! 30 ⁰ C,

V yyy. iiU ^ uuoit} !. uiiiuuitn uv / LuXvA -i. ^ _ w v /, u.U-1.

In the next stage, the lactone of the formula d is treated with a vinylic agent, for example with vinyl magnesium chloride. ,-vinyl-2 tetraliycLropyran-2-ol obtained, for example in tetrahydrofuran, preferably from -40 to -70 ⁰ C to give a tautomeric mixture (compounds e and e ^) of 6 ~ (3 ~ cyanopropyl) ». This reaction is highly selective in that the reactive nitrile group is not impaired by the vinylating agent under the carefully observed reaction conditions.

The next stage consists in finding the tautomeric mixture of e, and e _? treated with either water, a hydrohalic acid, a lower alkanol or a primary or secondary Arain, for example diethylamine or Kethy1-bensylamine. The reaction is preferably carried out in tetrahydrofuran and at temperatures between about 10 ° and 30 ⁰ C.

The tautomeric mixture obtained corresponds to f, and fp the tautomeric mixture IHd, in which R_ 3-cyanopropyl and η the number 2 means.

The compounds of the formula IHa or IHb, wherein η denotes the number 1 or 3 can be prepared in an analogous manner.

Compounds of the formula II in which R _{v is} hydrogen can also be obtained in accordance with the reaction class A. Here, a vinyl kötori of formula VI is reduced to vinyl diol VII using a chemical reducing agent. As chemical reducing agent hiebei complex metal hydrides, such as lithium aluminum hydride can _t

309809/1183

or 'Sodium-Ms ~ 2-methos: yethoxy-alanjiniumijydrid can be used. The rodtion can be carried out in an inert organic solvent, for example a hydrocarbon, for example benzene or toluene; in ethers such as diethyl ether or tetrahydrofuran, or the like. Be carried out. The temperature may be between about -20 ° and about 50 ⁰ C.

The vinyl diol VII is then oxidized to the ketone IHb-I. Manganese dioxide can expediently be used as the oxidizing agent will. The reaction can be carried out in any "any organic solvent, for example in hydrocarbons, such as Benzene or toluene. The reaction is preferably carried out in the presence of an organic amine, in which case the intermediately formed vinyl ketone of the formula IIIa-1 in the form of its Mannich bases Addition product of the formula IIId-1 can be taken. Suitable amines are open-chain or cyclic secondary organic amines, such as diethylamine, pyrrolidine, piperidine and the like. The intermediately formed vinyl ketone of the formula HIa-I can also be used as an addition product with a hydrogen halide acid, for example hydrochloric acid or hydrobromic acid be taken to produce the corresponding halogen ketone Formula IHb-I to deliver. The halogenice tones of the formula IIIb-1 can be converted back into the vinyl ketones of the formula IHa-I by treatment with a weak base. Suitable weak bases are tertiary organic amines, e.g. pyridine, triethylamine and the like. This elimination reaction may be in an inert organic solvent such as a hydrocarbon e.g. benzene or toluene carried out at a temperature between approximately 0 ° and 10 ° 0 will. The reaction can also be carried out in the absence of an additional solvent, in which case the amine used as a solvent.

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Gr.:;i-Lr,cj oiuer other Auaführun ^ nforni Irör ^ on Halo ^ erjkctonc cdcr / blinke tone flcr Pcrniül V ;; u compounds of the form VTIT lre'U-Ti i .. '. ;; i ori; Tir? R «'l.on.- M. ^r ; V &'l'! *. \ Io ~) .orun ^ sniit Ι · ^! can "boi— npi.olovroj rjn r} '5." tl «re Alkanols, r-, E. Ke übanol, .Aetjirno.l _; Bat ■■ - :.] ιο

nn <1 like; niccloro Al]: ylGKd.iolo,: -jB Aethyle.nclycol, 2,3-Butyl eil; 'Iy ool, 1,2-Buty] e.ngly col, 1,2-Propy lenc.1 y col uiiu like. ; o-arylene cliols,% «B. Catechol; lower alkyl Ori.hoXorjij.lato, ζ.B. Ti-imethylortlioforrulat or TrläthylortholOr; niat and d ^ l, veru'orjdct v: earth, the totalization is in the present. ej.ner strong sani '"? _r executed Geeignste strong acids are beispielrn: eir.e mineral acids such as hydrochloric acid, sulfuric acid and dfl .; organic sulfonic acids, aB p-toluenesulfonic acid and the like; Lewis acids, see Bortrifluoj.'id. The metalization can be carried out directly in an inert organic solution. Suitable inert organic solvents are, for example , hydrocarbons, for example benzene or toluene; lower alkanols, for example methanol or ethane 1, ethers, for example diethyl ether or tetrahydrofuran; and the like. Ketalisiei * can ungsreaktion at a temperature avrisehen about O ⁰ C and about 15O ⁰ C are performed. The resulting water can be removed either by aaectropic distillation or by reaction with a dehydrating agent, for example an alkyl orthoflorate.

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BATH ORIGINAL

Reaction scheme A

R ¹ O ₂ C-

Vn ■

VI

O CD 00 O CO

VII

Illa-l

, 11Ib-I

Ha

R ¹ O ₂ C

'2

OH i

where X "and η have the above meaning, Z is a ketalized Oxognj.ppe and R ^{1 is} a lower alkyl group.

VIII

> n

IX

2241 ILO

The ester group of a Ytirbindan.; -; VIII Latin, durm be reduced, with nan receiving a compound of i'Oirne.l TX. Old; Reducing agent, any suitable chemical reducing agent can be used, with "complr -!" G metal hydrides, e.g. for example, benzene or toluene;.. are carried out in an ether, such as diethyl ether or tetrahydrofuran and the like the temperature door, wherein the reduction is carried out can be between about -20 ° and about 50 ⁰ C.

In a pole step, the ketal of the formula IX is decetalized to a compound of the formula IIIb-1 by treating the ketal with an aqueous acidic medium. Suitable acids are, for example, mineral acids, for example hydrochloric acid or sulfuric acid; organic sulfonic acids, for example p-toluenesulfonic acid - _f alkanecarboxylic acids, for example acetic acid and the like. If desired, an organic solvent can be used as an additional solvent. Particularly preferred additional solvents are organic ketones, for example acetone. The deketalization may be carried out ⁰ C to about 150 ⁰ C at a temperature of about O.

The ketal of the formula IX can be converted into a new, one-step reaction with thiourea .Spirothiazine of formula xla can be converted. The for Reaction conditions suitable for this conversion are the same as those described above for the conversion of the compound of the formula IHa or IHb into the compound of the formula II have been described, but iia must be in the reaction medium Acid be present. The acid can be a mineral acid such as hydrochloric acid; an organic sulphonic acid, e.g. p-toluene ~

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BAD OBiGiNAL

2241U0

sulfonic acid or a lower alkanecarboxylic acid, e.g. acetic acid be. According to a preferred embodiment, an alkanecarboxylic acid was used as the solvent, "whereby acetic acid is preferred. The acidic acid addition salt formed can be disassembled in the usual way.

Furthermore, compounds of the formula

NO",

where RLV has the above meaning and R'p is lower alkyl, lower alkenyl, Aryl or aryl-lower-alkyl and R, and η have the above meaning,

directly to compounds of the formula IIIa or IHb Reaction with the appropriate Ν, Ν-disubstituted thiourea can be obtained in the manner described above for the preparation of the compounds II.

Compounds of the formula Id can also be prepared in this way from the corresponding N-monosubstituted thioureas can be obtained.

Optically active compounds of the formulas I and II can be obtained by optical resolution of a racemic compound of formula I or formula II or by using an optically active starting material of formula III will.

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The optical resolution of racemic compounds of the formulas I and II can be carried out in the usual way, for example by fractional crystallization of the diastereomeric additive salts of the compounds I and II with optically active acids. Suitable optically active acids are strong acids such as organic sulfonic acids, e.g. Antipodes of camphorsulphonic acid, bromocampherulphonic acid and the like; and carboxylic acids such as the antipodes of tartaric acid, malic acid, metnoxyacetic acid and the like.

Surprisingly, it has been found that when racemic compounds of the formula I or II, which only one optically active center (namely the spiro carbon atom) treated with a strong optically active acid, a greater amount of either diastereomeric salts are obtained than is theoretically possible corresponds to what an indication is that this is a dynamic There is an imbalance between the enantiomeric forms in the presence of the strong acid. Particularly preferred strong optically active acids are the antipodes of camphereulfonic acid.

The optical cleavage of the compounds of the formulas I and II takes place under the customary reaction conditions and with the mediation of the usual solvents. Suitable Solvents are, for example, lower alkanols, e.g. methanol or ethanol; lower alkyl ketones such as acetone; Acetonitrile; Ethyl acetate; and the like

It has also been found that an optically active compound of the formulas I or II, which is only an optically having active center, is racemized by treatment with a strong optically inactive acid. Suitable strong, optically inactive acids are, for example, mineral acids, e.g., hydrochloric acid and sulfuric acid; organic

309809/1183

Sulfonic acids, for example p-toluenesulfonic acid; and the like. The amount of acids used can be in a broad range between about 0.1 mol fo "to more than 100 mol $, based on the substance to be racemized. Generally from about 1 to about 20 mole percent acid is preferred.

Suitable solvents are lower alcohols, for example methanol or ethanol; Alkyl ketones, for example acetone; Acetonitrile; Ethyl acetate; Dimethylformamide or mixtures of these substances with water. The reaction temperature may sswischen about 0 ° and about 150 ⁰ O are. A preferred temperature range is between about 50 and about ^100.degree .

The compounds of the formula I have an analgesic, anti-inflammatory, anti-pyretic and diuretic action. Both the anti-pyretic and the analgesic effectiveness can be determined, for example, on the rat paw inflamed with yeast. Here, a compound with an EDe ₀ of less than 200 mg / kg po is considered to be active. The following compounds according to the invention were tested by means of this test and found to be effective:. · ._.

Rac. 2-Phthalimido-7-oxa-3-thia-l-azaspiro [5.5] -undeo-1-ene.

Rac. 2-p-fluorobenzamido-7-oxa-3-thia-l-azaspiro [5.5] - · " undec-1-en. ·

Rac. 2-cinnamamido-7-oxe-3-thia-1-azaspiro [5.5] undec-1-en. '·. .

Rac. 2-p-Nitrobenzamido-7-oxa-3-thia-l-azaspiro [5.5] -undec ^ l-ene.

Rac »2- (3,4-dimethoxybenzamido) -7 ~ oxa-3-thia-1-azaspiro [5« 5] undec-1-en. ·

Rac. 2-p ~ cyanobenzamido-7-oxa-3-thia-1-azaspiro [5 x 5] -undec-1-en.

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22A1UO

Rac. 2-p-methylbenzamido-7-oxa-3-thia-1-azaßpiro [5. ^l j ] undec-1-en.

Rac. 2-m-fluorobenzamido ~ -7 - oxa -? - thia-l ~ a & aupLro [5 · 5 ] -undec-1-en.

The above test results show the usefulness of the compounds of the formula I as antipyretic and analgesic Middle.

The fact that the compounds according to the invention can be used in therapy is underlined by their low toxicity. For example, the IDp is ~ from rac. 2-p-Fluorobenzamido-7-oxa-3-thia-1-azaspiro [5.5] -undec-1-ene when administered intraperitoneally to mice more than 400 mg / kg.

The compounds according to the invention can be used as remedies, E.g. in the form of pharmaceutical preparations that are used in a mixture with one for the enteral or parenteral application suitable pharmaceutical, organic or inorganic inert carrier material, such as water, gelatin, lactose, starch, magnesium stearate, Talc, vegetable oils, rubber, polyalkylene glycols, Vaseline U8if. contain. The pharmaceutical preparations can be in solid form, e.g. as tablets, coated tablets, suppositories, capsules, or in liquid form, e.g. as solutions, suspensions or enailions are present. If necessary, they are sterilized and / or contain auxiliaries, such as preservatives, Stabilizing, wetting or emulsifying agents. You can auoh contain other therapeutically valuable substances.

Unless otherwise stated in the following examples, the compounds described are each racemates.

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Beis piel .1

12.65 g of 6-phenyl-2-vinyl-tetrahydropyran-2-ol are mixed with 4.5 g (0.059 mol) of thiourea and 50 ml of glacial acetic acid and the resulting mixture is stirred at room temperature for 18 hours. The orange thus formed solution is evaporated at reduced pressure to a syrupy residue, which with ether and 1 η aqueous hydrochloric acid is treated, Jb in this case forms a dense precipitate which abfi.ltriert, washed well with ether and set aside. the united with the washings FiItrat is separated into an ether layer and an aqueous layer. The aqueous layer is extracted again with ether and set aside. The combined ether extracts are washed with sodium chloride solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure, 4.2 g of neutral by-products being obtained in the form of an orange oil.

The solid and the aqueous acidic solution which had been set aside are combined and with a 10 ^ igen aqueous sodium hydroxide solution is alkaline posed. Customary work-up with methylene chloride gives 11.4 g of an orange, semi-solid mixture of isomers of 2-amino-8-phenyl-7-oxa-3-thia-1-azaspiro- [5.5] undec-1-ene. A sample of this material (10.9 g) is dissolved in 25 ml of hot acetonitrile, whereupon 5.3 g maleic acid, dissolved in 25 ml hot acetonitrile, clogs. The resulting solution is evaporated under reduced pressure and the evaporation residue is triturated with ether leaving a solid. Filtration and washing with ether give a light brown solid (Melting point 159-164 °), which is a mixture of the maleates of the above two isomers. This material is digested in 75 ml of boiling acetonitrile and then

309809/1183.

2241U0

cooled and filtered. After drying you get one of the two isomeric maleates in the form of solids with a melting point of 169-170 °.

Analysis calculated for Ο ^ ϊ ^ Έ ^ ΰ: C, 57.13; H, 5.86; N, 7.40; S, 8.47 Found: C, 57.45; JI, 5.93; H, 7-53;

S, 8.47.

In another experiment, the crude base mixture (3.1 g) is triturated with ethyl acetate, ν.τ / where 0.79 β of a white solid with a melting point of 164-165 ° is obtained. Recrystallization of a sample obtained in this manner from acetonitrile gives an analytical sample of the other isomers in the form of a weisoen solid having a melting point of 166-167 ⁰ C.

-i

_{5 35OOt 54OO} ^ _{167Oj 165O> 1610 cm}

Max

² 5 203 (c 19200), 255 (290), 26.1 (182) πιμ; Max

⁷ x ³ ' ⁶ x ⁰ ' ⁴ x ⁶ ' ² ' ⁹¹ ' ¹ ^ ⁰¹ ' ^Ppm: mass spectrum: m / e 262 (M ⁺ ), 234 (M-28).

Analysis calculated for C ₁₄ IIj ₈ N ₂ OS: C, 64.10; H, 6.92; N, 10.68;

S 12 20

Found: C, 64.31; H, 6.86; N, 10.74;

S, 07/12.

The filtrate obtained after filtering off this second isomer is diluted to 100 ml with 60 g of aluminum oxide stirred and filtered. Evaporation of the filtrate gives 0.4 g of the first isomer, rich on standing recrystallized. Recrystallization from a mixture of benzene and hexane gives an analytical sample in form a white solid with a melting point of 102-103 °.

309809/1183

>> ^CIIC1 3 3500, 3400, 1630, 1580-cm " ^1. ■

Max

3400, 3300, 3250, 3125, 1640, 1600, 1580 cm "¹; max -.

A ° 2 ^{H 50} H 206 m \ i (ε 16000); S ™ ¹ ? 8.30, 5.11, 4-50, ·

infl.
3.16, 2 ppm; Mass spectrum: m / e 262 (M ⁺ ), 234 (M-28).

Analysis calculated for C ₁ .H ₁₈ NpUS: C, 64.10; H, 6.92;

1 \ Γ, 10.68; S, 12.20.

Found: 0.64.27; H, 6.85;

N, 10.60; S, 07/12.

The 6 "Phcnyl-2" used as starting material vinyl-tetrahydropyran-2-ol can be obtained as follows:

A solution of 10.4 g (0.059 mole) α-phenyl-JT-valerolactone in 150 ml of dry tetrahydrofuran is added with stirring and cooling in a dry ice-acetone bath with 50 ml (0.1 mol) 2M vinyl magnesium chloride in tetrahydrofuran dropwise added for 25 minutes, the internal temperature being kept between -50 and -60 °. The lactone slowly dissolves and the resulting solution is stirred at -70 to -70 ° for 15 minutes. Compartment with careful, dropwise addition of 10 ml of methanol is the reaction mixture to a mixture of Poured ice and a saturated magnesium chloride solution and worked up with ether, 12.65 g of crude 6-phenyl-2-vinyl-tetrahydropyran-2-ol (alternative name: 7-phenyl-hept-l-en-7-ol-3-one) in the form of a viscous yellow Oeles receives.

The ε-phenyl-ε-valeroacetone (melting point 72-74 ° ö) used here can be obtained by reducing 4-benzoylbutyric acid with sodium borohydride and recrystallization from benzene / hexane.

309809/1113

2241 HO

pj.ol · 2

The Mannichbüue 6-Pht; fiyl-2 - (? - d: iJithvlami; -i <> ethyl) -tetrahycTro-pyrr? N ~ 2-ol is prepared by treating the. crude 6-J'henyl-2-vinyl-tetrahydropyran-2-ol with dialy thy lar / dn hear. This crude Mannich product is purified by extraction with acid · to give a yellow oil.

A mixture of 1.55 g (0.0056 Hol) of the Ilannich base obtained in this way, 0.44 g (0.0058 mol) of thiourea, 5 ml of glacial acetic acid and 15 ml of toluene is stirred and refluxed for 75 minutes. The solution obtained is cooled, diluted with ether and treated with 60 ml of 3 η aqueous HCl. The thus precipitated precipitate is filtered off _f wherein 1.2 g of a solid having a melting point of from 2 ^ 0 to 231 ° (dec.) Is obtained. This material is made basic with 10% aqueous sodium hydroxide solution and worked up in the usual manner with methylene chloride, 1.1 g of a mixture of the two isomers obtained according to Example 1 being obtained. Stirring with benzene and filtration gives 0.394 g of the pesticide with a melting point of 160-161 ° _t, which essentially represents the second isomer. Evaporation of the filtrate gives 0.25 g of a solid with a melting point of 102-103 °, which is essentially the first isomer.

Example 3

The obtained according to the below mentioned available 6-methyl-2-vinyl-tetrahydropyran-2-ol is reacted with 12.63 g | _f treated 0 166 mol) of thiourea and 100 ml of glacial acetic acid. The reaction mixture is stirred at room temperature for 20 hours and the orange-colored solution obtained is evaporated under reduced pressure. The obtained eyrupfönnige residue is

309809/1183

. - 27 -

with Aether wiO. 1 η was kv · .; ·; Ογ Scüzsixure treated. Bio-aqueous layer is separated off and washed once with Aethc-.r and then rolled aside. Pie combined .A other extracts are once with "Kiiti'iisrac.hloridlööv.n ^ gewa.GC.ben, dried over Magnesriιγ · ωsUli'at, filtered and clipped under reduced pressure, with 9.5 g noutralor Jiebsnprodokte in the form of a Oeles receives.

I> ± e beforehand at! -8-methyl-7-oxa-3-thia-l-azaspiro [5 «5] -undec-1-eii is obtained. This material is rubbed with ether and cooled in the egg tank. Filtration gives 1.8 g of a slightly yellowish color. Fatty substance (melting point 114-115.5 °). Through thin layer chromatography it can be determined that this is predominantly an isomer.

By evaporating the combined ether filtrates and v / aschwäscer, 18.4 g of a yellow oil are obtained represents a mixture of isomers *. This is in 100 ml of ether dissolved and treated with a solution of 10.7 g of maleic acid in 80 ml of ethyl acetate. The resulting mixture is treated with 100 ml of ether and brought to crystallization. After cooling, the deposited precipitate is filtered off, washed with ether and dried, whereby one 22.5 g of a yellow solid are obtained. Recrystallization from 40 ml of acetonitrile gives 17.2 g of one whitish solid with a melting point of 135-144 ° »(mixture of isomeric maleate ·.) · ..

Analysis calculated for C ₁ QH ₁₆ N ₂ OS 1 CH ₄ -O .: C, 49.36 »H, 6.37; N, 8.06; S, 10.12. \ .... . '

309809 / 1.1.8 3,.

22A1U0

Found: C, 49.26; H ₁ 6.28; N ₁ 8.85; S, 10.01.

In another experiment the crude isomerone is turned off. (3.6 g) stirred with benzene and filtered, whereby one obtains 0/35 g of a solid, whose diirin layer chromatography is obtained indicates that it is essentially unthat Pure avreite Iüoaiere acts. Umlcristalli3ation from Benaol, which contains a few drops of acetonitrile gives a white pest with a melting point of 144-145 °

_{5 35OO>54OO> 165O} ^ _{1625> 1580 cm} -i.

JXl cX J \.

J ^ ⁵ 202 _Μ μ (ε 19050), X ^ ^HC1 207 πιμ (12650), ^{227 m} * ^{(ε 8000);}

1.20 ppm;

Mass spectrum: m / e 200 (M ⁺ ), (Μ-28).

Analysis calculated for CqH ₁₆ N ₂ OS: C, 53.98; H, 8.06;

N, 13.99; 3, 15.98.

Found: C, 54.04; H, 8.15;

N, 13.83; S, 15.74.

The combined mother liquors obtained after the above filtration are evaporated and the residue is filtered through Purified column chromatography on 1 kg of A3-uminium oxide. After development with 700 ml of an ethyl acetate-triethylamine mixture (9: 1), the bands are diluted with methanol, whereby 1.1 g of the first isomer, 0.5 g of the second isomer and 0.6 g of a mixture are obtained. The thus obtained oily first isomers cannot be made to crystallize. It is treated with 0.58 g of maleic acid and that maleate obtained in this way recrystallized from ethyl acetate and acetonitrile, a white pesticide with a Melting point of 139-141 °.

309809/1 183

_ 29 -

X ^C 2 ^H 5 ^OH 209 κμ (ε 26500).

max ■.

Analysis calculated for C ₁₃ H ₂₀ F ₂ O ₅ S: C, 49.36; H, 6.37;

Κ ",. 8.86; S, 10.12. '

Found r C, 49.47; H, 6.5%;

N, 8.75; S, 10.14.

The base released from this maleate is an OeI.

ScJ ₁ ), 1580 cnT ¹ ;

Max

^ C ₂ H ₅ OH 204 (ε 8715); ^ SSiS 4.55,4.13,3.00, max

1.10 ppm; Mass spectrum: m / e 200 (M ⁺ ), 172 (M-28).

The starting material used in the above procedure can be obtained as follows:

. A solution of 18.9 g (0.166 mol) of S- methyl- £ -valerolaoton (prepared from 4-acetyl butyric acid by reduction with sodium borohydride) in 100 ml of dry tetrahydrofuran is heated to -60 ° in a dry ice-acetone bath while stirring cooled while 150 ml (0.3 mol) of 2M yinyl magnesium chloride is added dropwise over 20 minutes. The temperature is kept below 45 °. After stirring for 10 minutes at -60 °, the mixture is carefully decomposed by the dropwise addition of 35 ml of methanol and then poured onto a mixture of ice and a saturated aqueous ammonium chloride solution. The usual work-up with ether gives 6-methyl-2-vinyl-tetrahydropyran-2-ol (or 7-hydroxyoct-l-en-3-one).

309809/1183

224ΊΗ0

A mixture of 10 g (0.0465 LIoI) of egg wanrri c'ibar: e 6-methyl-2- (2-dieth, ylKTiinoäthy.l) -tetrahydropyran -.?- ol (prepared by Ifaootsung the according to Example 2 ez The old vinyl additive with methylamine), 3.65 g (0.040 mol) of urea, 35 ml of glacial acetic acid and 105 ml of toluene is refluxed with stirring for 75 minutes. The solution obtained is cooled and extracted with 3 η aqueous hydrochloric acid. The aqueous, acidic extract is made alkaline with 10% aqueous sodium hydroxide and worked up with ether in the usual way, 6.9 g of the isomer mixture obtained in Example 3 being obtained. Stirring with benzene and filtering gives 1.65 g of a solid which consists essentially of the second isomer. The mother liquors essentially contain the first isomer.

Example 5

A mixture of 14.0 g (0.07 mol) of 2- (diethylaminoethyl) tetrahydropyran-2-ol, 5.6 g (0.073 mol) of urea, 70 ml of glacial acetic acid and 220 ml of toluene is refluxed with stirring for 75 minutes heated. The solution obtained is cooled and extracted with 1 η aqueous hydrochloric acid. The aqueous acidic extract is made alkaline with 10-6 aqueous sodium hydroxide and worked up in the usual way with ether to give 10.7 g of a yellow solid. Recrystallization from 60 ml of ethyl acetate gives 7 »4 g of 2-amino-7-oxa-3-thia-1-azaspiro [5.5] -undec-1-en with a melting point of 138-140 °. Umkristalli- eation from ethyl acetate gives an analytical sample in the form of a white solid with a melting point of 139-140.5 °.

309809/1163

- 21 -

2241H0

TfRr 1

V ":; 3375, 3300, 3250, 3150, 1640, 1590 cm ~;

Λ§2? ' ^ν ~ Eaäafcsorption 200 ημ (ε 10200); Checkout spectrum: m / e 186 (H ⁺ ), 158 (Μ - 28).

Analysis calculated for CgFL JT ₃ OS: C ₁ 51.60; H, 7.58;

IT, April 15; S, 17.19.

Found? 0, 51 = 68 ^ H, 7.70;

Ii, 15.25; S, 17.44 ·,

The corresponding maleate is obtained as a colorless solid with a melting point of 164-165 ° ^ crystallization from ethane oil.

CXOH ■ max ^{208 1ημ (ε} 27400),

Analysis calculated for CoH _n JNF ₀ OS.C, HO .: C, 47.68; H, 6.00; N, 9.27; S, 10:59.

Found: C, 47.41; H, 5.78; E, "9.18; S, 10.71.

The 2- (2-diethylaminoethyl) -2-hydroxy-tetrahydropyran used here as starting material can be made as follows;

25.2 g of 6-heptane-1,5-diol in 1,2-dichloroethane under a nitrogen atmosphere and with cooling with 100 ml Diethylamine and 208 g of activating magnesium dioxide treated. Stir each 1 day at room temperature under a nitrogen atmosphere The mixture is filtered and the residue is washed with benzene. The filtrate is evaporated and one obtains a crude product in the form of a brown oil. This crude product can be extracted with dilute hydrochloric acid, Neutralization and repeated extraction can be cleaned with an organic solvent. By cleaning on one An analytical sample is obtained from aluminum oxide column

309809/1183

2241H0

■ - 32 -

2- (2-Diethylaminoethyl) -2-hydroxy-tetrahydropyran.

Analysis calculated for C ₁₁ H ₂ -JJO ₂ : C, 65-63; H, 11.52;

N, 6.96.

Found: C, 65.80; H, 11.52;

N, 6.69-

The 2-amino-7-oxa-3-thia-l-azaspiro [5.5] and cc-l ~ en can be obtained by reacting 2- (2-chloroethyl) -2- (4-hydroxybuty] ) -l, 3-dioxo3.an with thiourea and ethyl acetate.

Example 6

A solution of 0.15 g (+) - 2-p-fluorobenzamido-7-oxa-3-thia-l-azaspiro [5.5] undec-l-en ([a] _D + 33.27 ° (c = 1, CHCl-)), prepared according to Example 31 »and 0.01 g of p-toluenesulfonic acid monohydrate in 5 ml of ethanol is heated on a steam bath for 3.0 minutes and then poured into a saturated aqueous sodium bicarbonate solution. The mixture is extracted with methylene chloride and the extracts obtained are washed with sodium chloride solution, dried, filtered and evaporated under reduced pressure, 0.142 g of rac. 2-p-fluorobenzamido-7-oxa-3-thia-l-azaspiro ~ [5-5] undec-l-en as a colorless pesticide with a melting point of 137-149 °; [a] _D = 0 ° (c = 1, CHCl-) obtained.

Example 7

A solution of 0.56 g of a crude mixture of isomers the aminothiazines as obtained according to Examples 1 and 2 in 3 ml of acetic anhydride and 6 ml of pyridine is left to stand at room temperature for 19 hours and then evaporated under reduced pressure. The residue is treated with saturated aqueous sodium bicarbonate and extracted with ether. The ether layer is separated

309809/1183

and the aqueous layer is extracted once with ether. The combined ether extracts are three times with In aqueous hydrochloric acid and the combined acidic extracts are washed with 3 η aqueous sodium hydroxide solution made alkaline and worked up in the usual way with ether, 0.531 g of a colorless mass which is a mixture of the isomers of 2-acetamido-8-phenyl- 7-oxa-3-thia-l ~ azaspiro [5.5] undec-l ~ en contains.

0.876 g of the material thus obtained are an Chromatographed 45 g of silica gel. The one with a benzene-ether mixture (4: 1) eluted fractions give 0.547 g of a pure Isomers in the form of a colorless glass-like substance which cannot be made to crystallize. subject drying this substance for several days under high vacuum

an analytical sample is obtained. 'χ ⁰ ^ 5 ° ^Ε 208 (13980),

Max

235 (7250), 262 (116 ^ i;? ³⁰¹ 224 (II5OO), 244 (12200) ιημ;

3400, 1700, 1595, 1550 cm ""¹; ^ gS 2.14, 2.75,

3.51, 4.76, 7.30 ppm;
Mass spectrum: m / e 304 (M ⁺ ).

■ Analysis calculated for C ₁₆ H ₂₀ IT ₂ O ₂ S: C, 63.12; H, 6.64?

N, 9.20; S, 10.53.

Found: 0.63.42; H, 6.71;

N, 9.03; S, 10.57. -.

The one with a benzene-ether mixture (1: 1) and ether eluted fractions give 0.180 g. of a pure second isomer in the form of a light yellow solid. By twofold recrystallization from benzene-hexane gives a analytical sample in the form of white needles with a

Melting point of 144-145 °. X ^Ö ^ 5 ° ^E 210 (10500), 264 (14250);

Max

_λ O ₂ H ₅ OH _{240 (7500) fflM λ} 0, IHHCl _{226 (11500) j 245}

max - max

309809/1183

ÖFtiGINAL INSPECTED

(12120), πιμ> ^ χ 3 3400, ¹⁷¹⁰ > ¹⁶⁰ ° f ¹ ^ ^{0 cm} ί ^ TMS ^ ² · ° 3 »2.77, 3.21, 4.56, 7.32 ppm; MasoenGpektruui: ω / e 304 (H ⁺ ), 276 (w-28).

Analysis calculated for C ₁₆ H ₂₀ N ₀ O ,. S: C, 63.12, H, 6.64; K, 9.20; S, 10.53 Found: C, 63.06; H, 6.73;

N, 9.22; S, 10.50.

Example B

1 g (0.05 mol) of the mixture of amines obtained according to Examples 3 and 4 is dissolved in 10 ml of pyridine, whereupon 5 ml of acetic anhydride are added. The resulting solution is kept at room temperature for 3.25 hours and then evaporated under reduced pressure. The evaporation residue is dissolved in ether and the ethereal solution is washed three times with aqueous hydrochloric acid. The combined acidic extracts are used once. washed with ether and the combined ethereal solutions discarded. The acidic solution is made alkaline with 10% aqueous sodium hydroxide, saturated with salt and worked up in the usual way with ether, 0.889 g of an isomer mixture of 2-acetamido-8-rcethyl-7-oxa-3-thia-1 -azaspiro [5,5] undec-l-en in the form of a yellow, resinous substance. This material was wildly chromatographed on 45 g of Silfcagel. The τ- with a benzene-Aethe mixture (4Ti) eluted fractions gave 0.152 g of a pure IsomerenJ with a benzene-ether mixture (1: 1) and eluted ether 'fractions giving 0.573 g of the second pure isomers.

A sample of the first isomer purified in this way is recrystallized twice from hexane, an analytical sample being obtained in the form of a white solid with a melting point of 13-114.5 °. ^^ 5 ^0H 220 (6250), 238 (6650), 266 (13800)

"*» ^ 2S ¹ 5 ³⁴⁰⁰ x ¹⁷⁰⁰ ' ¹⁵⁹⁵ x 2.72, 3.53, 3.78 ppm;

22A1140

Mass spectrum: κ / e 242 (M ⁺ ), 22? (M-15), 214 (M-28).

Analysis calculated for C _n H JPLO ₉ S: Q ₉ 54.53? H, 7.49; h _t 11.56; S, l'j _r 2 ± Found: C, 54.37; H, 7.66; U, 11.67; S, 13.41.

A sample of the purified one as described above second isomer is recrystallized twice from hexane-benzene, whereby a vre-issen plague st off with a melting point of

106-10) °. Λ ° 2 ^H 5 ° ^H 222 (6650), 239 (7150), 264 (14020);

max .. -O.UST HCl CHCl-

A 223 (11000), 245 (12180) ταμ; * ° 3400, 171O ₉ 1600, max n Ty - <- i max

1550 cm "¹;<£ ^ ³ 1.17, 2.07, 2.67, 3.19, 3.61 ppm | mass spectrum: m / e 242 (H ⁺ ), 227 (M ~ 15), 214 (M-128).

Analysis calculated for n ° ₁ ^H 8 ^N 'a ^{Si 0} 2 ^0> 54.53; H, 7.49? E, 11.56; S, 13.21. Found: C ₉ 54.72ι Η, 7.62; H,

11.59; S, 1 p.m.

Ex iel 9

A solution of 8,05 g (0.0435 mol) of that according to Example 5 obtained amino compound in 65 ml of pyridine and 40 ml of acetic anhydride is left to stand for 4.5 hours at room temperature and then evaporated under reduced pressure. Of the Evaporation residue is dissolved in ether and the ethereal solution is twice with 25 ml of 1.8N aqueous hydrochloric acid washed. The combined aqueous, acidic extracts are washed once with ether and the combined ethereal solutions discarded. The aqueous solution is cooled, with 40 ml of a 10 ^ igen aqueous sodium hydroxide solution to a pH ¥ ert of 8-9 adjusted, saturated with salt and worked up in the usual way. 9.5 g of the pale yellow are obtained here crystalline 2-acetamidor-7-oxa-3-thia-l-azaspiro [5? 5jundec-1-en. By chromatography on silica gel (elution with benzene ether and ether) and two recrystallization from benzene

30 9809/1183.

22A1H0

Hexane gives an analytical sample in the form of a colorless pesticide with a melting point of 110-111.5 °. Λ ° 2 ^Η 5 ° ^Η

ρτ.Τ (τι max

219 (70507, 236 (61570), 263 (13100) ιημ; ^ i; 3 34-00, 1710,

τ , P ¹ IY ¹ H max

1590, 1550 cm ¹ J «S ^ g 3 1.74, 2.12, 2.77, 3.49, 3.73 ppm

Mass spectrum: m / e 228 (M ⁺ ) 213 (M-15), 200 (M-28).

Analysis calculated for ⁰ IQ ¹¹ Ig ¹ ^ ° 2 ^Si ° * 52.62; N, 7.07;

N, 12.27; S, 02/14 Found: C, 52.40; H, 7.12; N,

12.28; S, July 14th.

Example 10

37.2 g of 6-ethyl ~ 2 ~ vinyl-tetrahydropyran ~ 2-ol are mixed with 17.2 g (0.226 mol) of urea and 140 ml of glacial acetic acid mixed. The mixture obtained is at room temperature for 16.5 hours stirred for a long time, after which the acetic acid is evaporated off under reduced pressure.

85 ml of 3N aqueous are added to the remaining residue Hydrochloric acid and 50 ml of water are added and the resulting mixture is extracted twice with ether. The ether extracts are discarded, while the aqueous solution is cooled in ice and the deposited precipitate is filtered off and washed with ice water is washed. After drying, 12.7 g of almost colorless 2-amino-8-ethyl-7-oxa -! - 3 ~ thia-l-azaspiro [5.5] undec-l-en-hydiochloride with a melting point of 213-21 / 1.5 ° (Decomposition). A sample of this is recrystallized twice from water, whereby an analytical sample is in the form of a white solid with a melting point of 211-212 °.

Analysis calculated for C ₁₀ H ₁₈ N ₂ OS.HCl: C, 47.89; H, 7.64; N, 11.17; S, 12.78. Found: C, 48.12; H, 7.75; N, 11.44; S, 12.31.

309809/1183

224114Q-. /

The acidic aqueous filtrate combined with the washing water is made alkaline with concentrated ammonium hydroxide and extracted three times with methylene chloride. The combined organic extracts are poured over anhydrous magnesium sulfate dried, filtered and evaporated under reduced pressure, 19 »8 g (41 $) of free amine (mixture of isomers) being obtained.

The starting material used here can be as follows obtained:.

A solution of 29 g (0.226 mol) of J-ethyl- <f-valerolactone in 130 ml of dry tetrahydrofuran is added dropwise while stirring and cooling to -60 ° (dry ice-acetone bath) 0.5 hours with 200 ml of 2.6M vinyl magnesium chloride in tetrahydrofuran offset, the temperature between -50 and -60 ° 'is kept. The mixture is stirred at -65 ° for 10 minutes .and then carefully treated with 30 ml of methanol, the Temperature is kept below -45 °. The mixture is then placed in a mixture of ice and ammonium chloride and the organic products are extracted three times with ether. The combined organic extracts are made once washed with sodium chloride solution over anhydrous magnesium sulfate dried and evaporated under reduced pressure, whereby 37.2 g of 6-ethyl-2-vinyl-tetrahydropyran ™ 2-ol (or 7-hydroxynon-l-en-3-one) in the form of an orange-colored oil.

Example 11

A solution of 1.42 g (6.63 raMol) of the crude / according to the example 10 base mixture obtained in 10 ml of pyridine and 6 ml

d is done for 4 hours at room temperature

and then evaporated water diminished in the bridge «, Der

is dissolved in ether and aw © i-times with "hydrochloric acid gawascheis» 5 ml on the one I ₉ IM aqueous

■ μ. ./. χ-ν ^ v ^. ■, · - ■■ "": .-. ■■

22A1U0

Wash water is extracted once with ether and the Acthor solution, which contains neutral impurities is discarded.

The acidic solution is made alkaline with potassium carbonate and extracted twice with ether. The essential extracts are combined and poured over anhydrous magnesium sulfate dried, filtered and evaporated under reduced pressure, 1.0 g of a yellow oil obtained from a Isomeric mixture of 2-acetamido-8-ethyl-7-oxa-3-thia-l-azaspiro [5 »5] undec-l-en exists.

This material is chromatographed on 50 g of silica gel. The fractions eluted with benzene ether (4ti) give 0.443 g of an isomer in the form of a pale yellow oil, which after crystallized after prolonged cooling.

Obtained by eluting with benzene-ether (1: 1) and ether one 0.358 g of the other isomer in the form of a pale yellow oil, which crystallizes after storage at 0 ° ".

By crystallization from benzene-hexane, one obtains analytical samples of the two isomers.

First isomer: whitish solid with a

Melting point of 79-80 °. UV:

0.1NHGl

225 ηιμ (ε 11350), 246 (12600).

p
UV: A ^C 2 ^H 5 ° ^H 222 πιμ (ε 7250), 238 (7380), 265 (15900);

IR: 3250, 1675, 1615 cm ^-1 ; M 3100-3400, 1700, 1595, 1550 cm " ¹ .

BMR: ί ^ g 3 3.54, 2.72, 2.11, 0.86 ppm.

MS: m / e 256 (M ⁺ ), 241, 227, 139, 43 (bases).

Analysis calculated for ^σ ΐ2 ^Π 20 ^Ν 2 ⁰ 2 ^{8: Cf} ^ ⁶ · ²² ? ^H r 7.86;

309809/1183

2241H0

N, 1Ο.93ί S, 12.51. - _{Found: c} , 56.40, · H, 7.80;

U, 10.81; S, 12.53.

Second isomer: colorless plague with an enamel point from 98-99 °.

U \ f

: A ^C 2 ^H 5 ^On 223 ΐημ (ε 6450), 243 (7150), 265 (14950);

Max

° '' ^umo1 224 ιημ (ε 11100), 247 (12000).

IR: -O ^ 3100-3400, 1595, 1555 cm ^X i ^ ™ Zr3 3400,

3100-3400, 1710, 1605, 1555 cm ""¹;

HTiHl

^ J 3 3.33, 3.24, 2.68, 2.08, 0.92 ppm

MS: m / e 256 (M ⁺ ), 241, 228 (M-28), 139, 43 (base).

Analysis calculated for ^c ₁ 2 ^H 20 ^N 2 ° 2 ^{S: C} * 56.22; H, 7.86; N, 10.93; S, 12.50. Found: C, 56.4HH, 7.90; N, 10.82; S, 12.46.

Example 12

A mixture of 6 g (32.2 mmol) of 2-amino-7-oxa-3-thia-1-azaspiro [5.5] iindec-1-en, prepared according to the information in Example 5, 4.63 g (33 mmol) of benzoyl chloride and 40 ml of dry pyridine is stirred at room temperature for 6 hours, The reaction mixture is then poured into a saturated Eatriumcliloridlösung and three extracted twice with ether The combined ether extracts vrerden with sodium chloride solution, dried _v dried over anhydrous magnesium sulfate and concentrated under reduced Evaporated pressure to obtain 9 _S 3 g of a crude product. This material is chromatographed on 100 g of silica gel. Elution with benzene-ether mixtures (91 to II2) yields 9.0 g of a pale yellow pesticide. By recrystallization from benzene-hexane, 8.2 g of rac 2-

309809/1183

Benzamido-7-oxa-3-thia-1-azaspiro [5,5] uridec-1-en.

UV: Λ ° 2 ^Η 5 ^ΟΗ 245 ωμ (ε 12000), 285 (24600); A Ο · ™ ⁰¹ max max

(25200).

1595 cm " ¹ .

3100-3300, 1605, 1555 cm "¹;>> ^ ⁰¹ J 1550, max max

HMR: <f ^CDC1 3 8.19, 7.39, 3.73, 3.54, 2.72, 1.78 ppm. TMS

MS: m / e 290 '(M ⁺ ), 262 (M-28), 105 (base).

Analysis calculated for ^ κ ^ Λ ^^ ^σ »62.05; H, 6.25; N, 9.65; S, 04/11; Found: C, 61.88; H, .6.31; N, 9.43; S, 10.85.

Example 13

The following connections are made by analogy with example 12 from 2-amino-7-oxa-3-thia-1-aza3piro [5,5] undec-1-en and the corresponding acid chloride obtained:

a) Rac. 2-p-fluorobenzamido-7-oxa-3-thia-l-azasPiror 5.51 ündec-1-en

Colorless pesticide, melting point 150.5-151.5 ° (from Ethanol or benzene-hexane).

UV: A ^C 2 ^H 5 ^OH 249 πιμ (e 11200), 290 (26300); A ° - ^BIHC1 max max

213 (8840), 258 (23600).

IR: ^ i ^KBr 3100-3300, 1610, 1555 cm " ¹ , max

HMRfef ^{olA / J} -3 12.75, 8.25, 7.07, 3.83, 3.67, 2.83, 1.90 ppm. TMS

MS: m / e (M ⁺ ), 280 (M-28), 123 (base).

Analysis calculated for CH FN ₂ O ₃ S: C, 58.42; H, 5.56; N, 9.08; S, 10.40.

309809/1183

. - 41 -

• - ■ 2241HQ

Found: C, 58.38; H, $ .80; ■ β, 8.93; S, 10.50.

The corresponding hydrooromide is a colorless plague with a melting point of 178-180 ° (from ethanol).

Analysis calculated for C ₁₅ IL ₁₇ M ₂ O ₂ SvHBr: G, 46.28; H, 4.66; N, 7 * 19; S, 8 _f 23. Found; C, 46.26; H, 4.70;

N, 7.11; S, 8.40. ■ ■ ·

b) Rac. 2-p-bromobenzene; amido-7 ^ oxa-3-thia-1-azaspirof 5 ♦ 5lundec-1-en

Colorless pest with a melting point of 128.5-129 ° (from benzene-hexane or ethanol).

W: A ^C 2 ^H 5 ^OH 257 ταμ (ε 15100), 295 (30200); A ⁰ * ™ ⁰¹ 220 m] x max max

(ε 10600), 267 (27000). ·. .

IE: ^ ⁰¹ * 3100-3300, 1595, 1555 cnf ¹ ; O ⁰¹¹⁰¹ S 1595, max max

1555 cm "..

NMR: S ^{GJ} 01} '} 12.75, 8.10, 7.54, 3.62, 2.79, 1.84 ppm. TMS

MS: m / e 368 (M ⁺ ), 340 (M-28), 144 (base).

Analysis calculated for C ₁₅ H ₁₇ BrN ₂ O _2, SRC, 48.79; H, 4.64; N, 7.58; S, 8.68; Br, 21.68. ( _found . _{σ> 48 # 90. Hf 4 # 75} .

N, 7.53; S, 8.99; Br, 21:33.

c) - ' Rac. 2-p-Methoxybenzamido-7 "Oxa-3-thia-1-aiaaspiro [ft _t ^ 1 and ndec-1-en

Colorless solid with a melting point of 104-107 ° (from benzene-hexane).

UV; λ ° 2 ^Η 5 ^0Η 221 mμ (ε 12250), 302 (35ΟΟΟ) _Ρ Λ ^{O4; ü3H} . ^G1 227 ιημ

max ■ '· max

(ε 15200), 257 (11500), 297 (22100).

3 0 9 8 0 9/1183

2241HO

IR: O ^KBr 3-100-330, 1605, 1555 cm "" ¹ , max

^χ 12.75, 8.20, 6.89, 3.82, 3.58, 2.77, 1.83 ppm. TMS

MR: ffi / e 320 (M ⁺ ), 292 (M-28), 111 (base).

Analysis calculated for C ₁₆ H ₂₀ N ₂ O ₅ S: C, 59.90; H, 6.29; N, 8.74; S, 10.00. Found: C, 59.93; H, 6.33; N,

6.67; S, 9.74.

ά) Rac. 2 ~ o-fluorobenzanido-7-oxa - 3 - thia-l ~ agaapir of 5. j? I undec-1-en

Colorless solid with a melting point of 95-96.5 ° (from ethanol).

UV: Λ ° 2 ^Η 5 ^ΟΗ 242 ΐημ (ε 10800), 283 (22200); jf ^{0 1111 101} 252 m) i max max

(ε 22300).

_{IR: 0} KBr 3IOO-33OO, 1605, 1555 cm " ¹ , max

Raman: (4880 A, powder) >> 1607, 1563, 1535 cm ".

Max

_{8 <05>} 7.20, 3.74, 3.52, 2.76, 1.78 ppm. TMS

MS: m / e 308 (M ⁺ ), 280 (M-28), 123 (base).

Analysis calculated for C ₁₅ H FN ₃ O ₂ S: C, 58.42; H, 5.56; N, 9.08; S, 10.40. Found: C, 58.11; H, 5.49;

N, 9.21; S, 10.57.

e) Rac. 2-p-chlorobenzamido-7-oxa-3-thia-1-aza3piroi5.5i undeo-1-en

Pale yellow solid with a melting point of 128.5-130 ° (from ethanol).

UV: X ^C 2 ^H 5 ^OH 252 πιμ (ε 14220), 293 (28400); A ° ^{# mi01} max max

216 ιημ (ε 9900), 264 (25420).

3098 0 9/1183

2241H0

IR: O ^ICBr 3100-3300, 1605t 1555 cn "" ¹ .

Max

HMR: «f- ^CDC1 3 8.13r 7.32, 3.71, 3.52, 2.72, 1.26 ppm.

MS: m / e 324 (M ⁺ ), 296 (M-28), 144 (base).

Analysis calculated for C, .H "ClN.OpS: C, 55.46; H, 5.28; N, 8.62; S, 9.87; "Found: C, 55.50; H, 5.20; K, 8.56; S, 10.15. - '■

f) Rac «2- (1-Adamantanylcarboxamido ) -7-oxa ~ 3-t h ia ~ l-az; aspirο [5 * 5] ^ ndec-l-en

Colorless solid with a melting point of 158-160 ° (from ethanol).

UV: Λ ° 2 ^Η 5 ^ΟΗ 237 πιμ (ε 7000), 270 (18000). ^ ° · ^1ΚΙίσι 230 mμ

max max

(ε 15150), Λ ° ^1Μ01 245 (12620). NS

^{IR: v)} max 3100-3400, 1585, 1555 cm " ¹ .

Raman: (5880 A, powder); O 1575 cm.

Max

HMR: "S ^^ 3.73, 3.43, 2.74, 1.8 ppm. TMS

MS: m / e 348 (M ⁺ ), 320 (M-28), 213, 135, 111.

Analysis calculated for C _nn H _OR N _o 0 _o S: C, 65.48; H, 8.09,

xy «co c. ά

N, 8.04; S, 9.20. Found: G, 65.56; H, 8.14; W, 7.98; S, 9.17.

g) Rac. 2-Qinnamamido-7-oxa-3 ~ thia-l ~ a zaspirof5 «5iunflec-l-en

Yellow.1: this viscous oil. The Ilydröohlorid, a whitish lily Solid, melts at 177.5-179 ° (from ethanol).

UY: A ^C 2 ^H 5 ^OH 223 µm (ε 14700), 311 (37000).

Max

309809/1183

22A1U0

. ^r 24ΟΟ-325Ο, 1710, 1630, 1595, 1570 cm \ max

Tim

NMR: "S- ^vJJOi 3 7.95, 6.79, 7.60, 7.43, 3.80, 3.53, 2.85" TMS

1.45-2.66 ppm.

Analysis calculated for C ₁₇ H ₂₀ N ₂ O ₂ SJlOl: C, 57.86; H, 6.00; N, 7.94ί S, 9.08. Found: C, 57.67; H, 5.79; N, 7.77; S, 6/9.

Example 14

A solution of 5 g (0.0308 mol) Ι, Ι'-carbonyl-diimidazole in 15 ml of dry tetrahydrofuran is stirred at room temperature, while a solution of 3.1 g (0.03 mol) of ethoxyacetic acid in 5 nil dry tetrahydrofuran added wiiu.Ee developed yourself gas; the resulting solution is stirred for one hour. A suspension of 5.6 g (0.03 mol) of 2-amino-7-oxa-3-thia-1-azaspiro [5.5] undec-1-ene is then added in 60 ml of dry tetrahydrofuran added over the course of 5 minutes and the resulting mixture is stirred at room temperature for 18 hours.

After adding 60 ml of water and 200 ml of saturated sodium chloride solution, the organic material is extracted three times with methylene chloride. The combined organic extracts are washed once with sodium chloride solution, over anhydrous Dried magnesium sulfate, filtered and evaporated under reduced pressure. 8.1 g are obtained in this way of a yellowish, oily crude product. ■

7 S of this material are chroma! 0-graphed on 200 g of silica gel. Elution with benzene-ether (1: 1) and ether-ethyl acetate (4: 1) gives 5.4 g of 2-ethoxyacctamido-7-oxa ~ 3-thia-laza3piro [5,5] undoc-3-ene in Fora of a yellow oeleo.

, 1700, 1600, 3555 cm 309809/1183

224IHO

A solution of this material in 50 ml of ethyl acetate vrird au a solution of 2.3 g of maleic acid in 50 ml of ethyl acetate and the resulting solution under reduced pressure vrird ^v evaporated. The white solid residue is recrystallized from ethyl acetate, giving 6 g of maleate with a melting point of 96-97.5 ° in the form of a white solid.

OT: A ^G 2 ^H 5 ^0H 212 ιημ (ε 20550), 266 (15620),

Max

mmS ^0W1 3 6 * 34, 4.20, 3.59, 2.90, 2.40, 1.83, 1.23 ppm. TMS

Analysis calculated for G ₁₂ H ₂₀ N ₂ O ^ SO ₄ H ^ O ₄ ! C, 49.48; H, 6.23; N, 7.21; S, 8.25. Found: 0.49.68; H, 6.34; N, 7.21; S, 8.28.

Example 15

It becomes rac «2-phenylacetamido-7-oxa-3-thia-l-azaspiro [5,5] undec-l-ene from 2-amino-7-oxa-3-thia-l-azaspiro [5,5] undec-1-ene and phenylacetic acid in analogy to the information in the example 14 manufactured. The free base is a yellowish oil.

3100-3400, 1710, 1600, 1550 cm " ¹ .

The maleate is a colorless solid with a melting point of 101-102 ° (from ethyl acetate),

ÜV: "X ^C 2 ^H 5 ^OH 209 ΐημ (ε 28050), 267 (16500).

Max

HMH: 6 ^{0Ι) σΐ} 3 7.30, 6.34, 3.86, 3.74, 3.46, 2.85, 1.54-TMS

2 * 58 ppm *

Analysis calculated for ^c ; ^ ⁿ 20 ^ 2 ⁰ 2 ^{S # Ci} 4 ^H 4 ⁰ 4 ^{: C>} 57.13 $ H, 5.75; N, 6.66; 3, 7.62, _{foundj Of 51t%} . _{} lf} ^ ₇₃ . _N>

6.65; S, 7.72.

30980 9/1183

22A1U0

A solution of 1 g (5.38 mmol) ii aza & piro [5 »5jundec-l'-en and 0.675 ΰ (5, f> 5 idMoI) phenyl-iaocyaiiiit in 20 ml of llethylene chloride is 1.5 hours with itaumtoripair stirred and then evaporated to dryness under reduced pressure. The evaporation residue is stirred with benzene, whereby, 1.4 g of a light brown solid are obtained, awei recrystallizations brownish crystals of racemisohem 2 ~ (3-hienyl) urei do-7-oyn.-3-thia-l-ap; aspiro [5,5] are obtained from methanol undec-1-en with a uclim melting point of 177-178 °.

UV: A ^C 2 ^H 5 ^0H 277 m | i (ε 20000); Λ ° - ^1NHC1 247 κμ (ε 17820). max max

. IRi ^^ 3 3425, 3100-3400, 1700, 1625, 1575, 1510, 1440, cm " ^1. ^

MS: m / e 305 (M ⁺ ), 213, 186, 158, 119 (base), 111.

Analysis calculated for C H.J 0 S: C, 58.99; H, 6.27; U, 13.76; S, 10.50. Found: C, 58.94; H, 6.26; N, 13.77; S, 10.37.

Example 17

A solution of 1 g (5.38 mmol) of 2-amino-7-oxa-3-thia-lazaspiro [5.5] undec-l-ene and 0.81 g (5.56 nmoles) of phthalic anhydride in 15 ml of dry Pyiidine is stirred at room temperature for 5 hours and then poured into a saturated sodium chloride solution. The resulting mixture is extracted three times with ether and the combined extracts are washed once with sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure.

309809/1 183

> - 47 -

The residue (0.9 g) is concentrated on 50 g of silica gel. chronographed. Elution with benzene ether (4il and 1: 1) gives 0.55 g of pure rac. 2 ~ Phthalimido-7-oxa-3 ~ thia-'l ~ azaspiro [5,5] undee-l-eii in Poxm of a colorless solid ·. After two recrystallizations from benzene-hexane, 0 _t 474 g of a colorless pesticide with a melting point of 166-167.5 ° are obtained.

W: Κ ^Ο ^ 5 ° ^Ά 220 mji (ε 49000), 293 (2345) ;, Λ ^C 2 ^H 5 ° ^H 238 ιημ max 'Sch

(ε 14000), 301 (2100).

IR: -O ⁰ ^ ⁰¹ J 1790, 1730, 1610, 1625 cm "" ¹ . Max

HMR: cT ^CDC1 3 7.81, 4.22, 3.67, 3.22, 1.74 ppm. TMS

MS: m / e 316 (M ⁺ ), 288 (M-28), 144 (base)

Analysis calculated for C ₁₆ H ₁₆ N ₂ O ₇ S; C, 60.74; H, 5.10;

N, 8.85; S, 10.13. Found: C, 60.51; H, 4.82; N,

8.56; S, 10.01.

This substance can also be converted into aich in a similar manner of 2-amino-7-oxa-3 ~ thia-l-azaspiro [5,5] undec-l-ene with phthaloyl chloride.

Example 18

A slurry of 0.624 g (0.013 mole) of a 5C "igen

oil -

Sodium hydride single dispersion in 12 ml of dry diethylformamide It is stirred while cooling with an ice bath while dissolving of 2.7 g (0.0118 mol) of 2-acetamido-7-oxa-3 ~ thia-l-azaspiro [5.5] ' undec-1-en in 30 ml of dry dimethylformamide dropwise added over a period of 10 minutes. It will Hydrogen is released and "the" mixture is stirred for 10 minutes at 0-5 ° and then for one hour at room temperature.

309 80.9 / 1 1 03

2241U0

The reaction mixture is cooled again in a Jüis bath while 1.45 nil (0.0125 mol) of benzyl chloride in 15 ml of dimethyl 1-fcrmamide is added over a period of 5 minutes. The ice bath is then removed and the mixture is stirred at room temperature for 4 hours, after which 3 ml of water are added. Did. resulting solution is evaporated under reduced pressure and the evaporation residue is taken up in ether and washed three times with 3N aqueous hydrochloric acid _t YOUr WaschwäBner are combined and extracted one time with ether. The ether extract is discarded.

The acidic extracts are mixed with 10 ^ aqueous sodium hydroxide solution made alkaline and then extracted three times with ether. The ether extracts are combined with sodium chloride solution washed, dried and filtered. Evaporation of the solvent gives 2.96 g of a yellow oil, which 2- (N-benzylacetamido) -7-oxa-3-thia-1-azaspiro [5,5jundec-1-en contains.

This substance is refluxed for 2 hours with stirring with 25 ml of 2N aqueous hydrochloric acid. After cooling down the device is made alkaline with 107 $ sodium hydroxide solution and extracted three times with methylene chloride. The United Methylene chloride extracts are washed once with sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. This gives 2.5 g of crude, crystalline rac. 2-Benzylamino-7-oxa-3-thia-1-azaspiro [5,5] undec-1-en. Recrystallization from ethanol gives 1.682 g of colorless crystals with a Melting point of 94-95 °.

Further recrystallization from ethanol gives a colorless solid with a melting point of 94.5-95.5 °.

309809/1183

2241 HO

UV: A ^C 2 ^H 5 ^OH 216 ιημ (ε 18,000). Max

IR: \) ^CHG1 3 3430, 1630 cm " ¹ , max

NMR: <r ^{C3} 01} 3 7.34, 4.50, 4.12, 3.56, 3.08, 1.71 ppm. TMS

MS: m / e (M ⁺ ), 248 (M-28)

Analysis calculated for C ₁₅ H ₂₀ N ₂ OS: C. 65.18; H, 7.29; N, 10.13; S, 11.60. Found: O, 65.51; H, '7.31; N, 10.12; S, 11.69.

Example 19 "·

Rac. 2-methylamino-7 ~ oxa-3-tMa ~ l-azaspiro [5,5] undec-l-en is in analogy to the information contained in Example 18 from ' 2-acetamido-7-oxa-3-thia-l-azaspiro [5,5 »] undec-l-en and methyl iodide obtain. The product is a colorless solid with a melting point of 107.5-109 ° (from ethanol).

UV: λ ° 2 ^Η 5 ^ΟΗ 210 ΐημ (ε 10000). infl. ·

IR: O ^CHC13 3450.1620 cm " ^1. max

mm-.S ^^ 4.20, 3.91, 3.57, 3.06, 2.83, 1.77 ppm. TMS

MS: m / e 200 (M ⁺ ), 172 (M-28), base peak.

Analysis calculated for CH ₁₆ N ₂ OS: C, 53.97; H, 8.05; N, 13.98; S, 4 p.m. Found: C, 54.14; H, 8.01, N, 14.04; S, 15.91.

Example 20

A solution of 3 g (0.0149 mol) of 2- (diethylamino-ethyl) -tetrahydropyran-2-ol, 2.28 g (0.015 mol) phenylthiourea,

309809/118 3

2241HO

15.ml of glacial acetic acid and 50 ml of toluene are stirred for 18 hours refluxed for a long time. The solution obtained is then taken under evaporated to dryness under reduced pressure. The binding steam residue is treated with ether and washed three times with dilute aqueous hydrochloric acid. The acidic extracts are combined and washed once with ether. The ether extract is discarded.

The aqueous acidic solution is mixed with 10 ^ aqueous Sodium hydroxide made alkaline and extracted three times with methylene chloride. The combined organic extracts are dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 2.1 g of a red resinous substance.

This substance is chromatographed on 100 g of silica gel. The fractions eluted with benzene ether (9: 1) give 0.922 g of a yellow crystalline material which is the desired Product received.

A sample of this material is recrystallized twice from benzene-hexane to give rac. 2-phenylamino-7-oxa-3-thia-l-azaspiro [5.5] undec-l-ene with a melting point of 103-104.5 ° (alternative name for this substance: rac. 2-phenylimino-7-oxa -3-thia-l-azaspiro [5.5] undecane.

UV: X ^C 2 ^H 5 ^OH 261 ΐημ (ε 12700); λ ^{0 # 3} ^ ¹⁰¹ 226 ιημ (ε 13000). max max

IR: ^ ^CHC1 3 3400, 1585 cm "¹; 0 ⁰¹¹⁰¹ S 1640, 1600 cm"" ¹ , max Sch

PTVT

NMR: <f ^u ; 5 7.18, 3.95, 3.65, 3.32, 2.74, 1.72 ppm. TMS

MS: m / e 262 (M ⁺ ), 234 (M-28), 111

Analysis calculated for C ₁₄ H ₁₈ N ₂ OS: C, 64.09; H, 6.91;

309809/1183

2241U0

* ' ¹⁰ '^{68; S '12} < ²² · Found: σ, 63.86; II, 6.84; Έ; ·

10.54; S, 12.37,

Example 21

The following substances are based on 2-amino-7-oxa-3-thia-l-azaspiro [5,5] undec-l-ene and either your corresponding Acid chloride according to the methods of example 12 or the corresponding acid according to the carbonyldiimidazole method obtained from example 14:

a) Rac, 2- (3-trifluoromethylbenzamido) -7-oxa-3-thia-l-azaspiro [5 «51undec-l-ene (acid chloride method)

Colorless pesticide with a melting point of 101-102 ° (from ethanol).

UV: A ^C 2 ^H 5 ^OH 241 πιμ (e 11200), 292 (23000); X ° ^1MG1 250 mμ (ε 23500). ^{max max}

IR: O ⁰¹ "3100-3400, 1620, 1605, 1560 cm" ¹ , max

HMR: «Γ" ^ - ^ 8.40, 7.54, 3.73, 3.56, 2.75, 1.80 ppm. THS

MS: m / e 358 (M ⁺ ), 330 (M-28), 173, 144 (base), 111.

Analysis calculated for C ₁₆ HI ¹ N ₃ O ₂ S: C, 53.62; H, 4.78;

TJ 7 R? S Ω QR

JM, (. Q ^, ο, ay:>, Found: C, 53.93; H, 4.89; N,

7.78; S, 9.19.

b) Rac. 2-m-fluorobenzamido-7 ~ oxa-3-thia-l-azaspiro [5,5iundec 1-en (carbonyldiimidazole method)

Colorless solid with a melting point of 85-86 ° (from ethanol).

UV: Z ^C 2 ⁿ 5 ^OH 245 ΐπμ (ε 11400), 285 (23800); Max ·

309809/1183

22A1U0

Max

IR: λ) ⁰¹ "3100-3400, 1610, 1555 cm" ¹ , max

NMR: ^ 3 12.70, 7.93, 7.29, 3.75, 3.60, 2.76, 1.80 ppm. TMS

MS: m / e 308 (M ⁺ ), 280 (M-28), 144, 123, Hl (base).

Analysis calculated for C ₁₅ H "JTLO ^: C, 58.42f H, 5:56; N, 9.08; S, 10.40. Found: C, 58.71; H, 5.70; N,

9.09; S, 10.28.

c) Rac. 2-o-chlorobenzamido-7-oxa-3-thia ~ l ~ aza-spiro [5.5] u nd ec-1-ene (acid chloride method)

Colorless pesticide with a melting point of 115.5-117 ° (from ethanol).

UV: X ^C 2 ^H 5 ^OH 245 πιμ (ε 9120), 287 (20500); Λ ⁰ '™ ⁰¹ 253 ηιμ ^{mx max}

(ε 18600).

3100-34.00, 1600, 1585, 1550 cm " ¹ .

Max

! JMR: S ^ ^0J -3 7.82, 7.32, 3.78, 3.55, 2.77, 1.70 ppm. TMS

MS: m / e 324 (M ⁺ ), 111 (base).

Analysis calculated for ^C ₁₅ ^H ₁ 7 ^C1Jii ₂ ^O 2 ^{Si c} »55.47; H, 5.28;

N, 8.62; S, 9.87. ^ Found: C, 55.56; H, 5.25; N, 8.60; S, 10.03.

d) Rac. 2- (2.416-Trimethylbenzamido) -7-oxa-3-thia-1-azaspiro [515] and 6c-1-en (acid chloride method ^

Colorless solid with a melting point of 120-121.5 ° (from acetonitrile).

309809/1 183

22A1U0

W: A ° 2 ^H b ^0H 272 πιμ (ε 17220); J ⁰ · ™ ⁰¹ 220 raμ (ε 17220), •• 251 (14800)? « ^RaaX

5100, 3200, 1650, 1620, 1530 cm " ¹ .

Max

NMR: «f ^ODG1 3 6.82, 3.78, 3.45, 2.80, 2.30, 2.25, 1.75 ppm. TMS _% . .

MS: m / e 332 (M ⁺ ), 317, 304, (M-28). 147 (base), 111.

Analysis calculated for O ₁₈ H ₂₄ N ₂ O ₂ S: σ, 65.03j H, 7.28; ^N * 8 x 43; S, 9.64. Found: C, 65.12; H, 7.29; N, 8.53! "S, 9.44.

e) Rac. 2 ~ p ~ Mtrobenzamido-7-oxa-3 ~ thia - l-azaspiror <? . 5 lundecl ~ en "(acid chloride method)

Pale yellow plague with a melting point of 170.5-172 ° (from acetonitrile).

'UV: A ^C 2 ^H 5 ^0H 244 mμ (ε 12800), 301 (22000); / (°' ¹ ^ ¹¹⁰¹ 265 ηιμ (ε 26050). ^{Max max}

IR: -O ³ ^ ¹ * 3IOO-33OO, 1580, 1555 cm " ¹ , max

HMR: ^ ⁰¹³⁰ ^ 12.72, 8.31, 3.80, 3.64, 2.80, 1.85 ppnu TMS

MS: m / e 335 (M ⁺ ), 307 (M-28), 150, 144, St.

Analysis calculated for C ₁₅ H ₁₇ N ₃ O ₄ S: C _f 53.72 | H, 5.H; N, 12.53; S, 9.56; Found: C, 53.50; H, 4.99; N, 12.64; S, 9.62.

f) Rac "2- (3.4.5-trimethoxybenzamido) ~ 7-oxa-3-thia-l azas piro [ 5 .5 | undec-l-en (acid chloride method)

Colorless plague with a melting point of 142 ₉ 5-143.5 ° (from Aethanoi).

30 9809/1183

2241 HO

ÜV: X ° 2 ^H 5 ^OH 298 ΐπμ (ε 25400); J ⁰ · ™ ⁰¹ 296 ημ (ε 1340O) ₁

Max

_IRj0 KBr 3200.5400, 1555

max ^υ

12.66, 7.52, 3.92, 3.90, 3.78, 3.60, 2.75, 1.Θ2 ppm. ™ ^S

MS: m / e 380 (M ⁺ ), 195 (base), 144, 111.

Analysis calculated for C ^^ OS: C, 56.83; H, 6.36; N, 7.36; S, 8.43; Found: C ₁ 56.85; H, 6.35; N, 7.30; S, 8.63.

g) Rac. 2- (3.4- ~ I ) iraethoxybenaamido) ~ 7-oxa-3-thia ~ l-aza Tp iro [5.5iundec-l ~ en (carbonyldiimidazole method)

Colorless pest with a melting point of 129.5-131 ° (from ethanol).

. UV: A ^C 2 ^H 5 ^OH 231 ΐημ (ε 14550), 286 (18450), 313 (22700) ', max

0.IMHCl ₂₅₅ (19700), 286 (11200), 315 (13150).

Max

3IOO-33OO, 1605, 1550 cm " ¹ .

Max

~ PT) PI

NMR; <r ^X 3 12.75, 7.83, 6.96, 3.92, 3.77, 3.59, 2.73, 1.80 ppm. ™ ^S

MS: m / e 350 (M ⁺ ), 322 (M-28), 165 (base), 144, 111.

Analysis calculated for C ₁₇ H ₂₂ N ₂ OS: C, 58.27; H, 6.33; N, 7.99; S, 9.15; Found: C, 58.38; H, 6.39; N,

7.96; S, 9.28.

h) Rac. 2-p-cyanobenzam: ⁱ do-7-oxa-3-thia ~ l-aza3piror5.5iundec1-en (3-acid chlori <i-method)

Colorless pest with a melting point of 170.5-309809 /1183

2241U0

172 ° (from acetonitrile).

W: A ^C 2 ^H 5 ^0H 248 ιημ (ε 17900), 292 (24300); Λ ⁰ ' ¹ ™ ¹ 255 m | t

max max

(c 31000).

IR: ^) ⁰¹ 3100-3400, 2225, 1595, 1555 cm "" ¹ ,

Max

r CDGl.

MMR: ό "^ 3 7/13, 8.56, 7.69, 3.77, 3» 58, 2.75, 1.82 ppm. TMS

MS: m / e 315 (M ⁺ ), 287 (M-28), 144, Hl (base).

Analysis calculated for CJ JO ₂ S! C, 61.01; H, 5.44f

N, 13.34; S, 10.18; Found: C, 60.86; H, 5.41; IT, 13.29; S, 10.19.

j) Rac. 2-p ~ n-Butoxybenzamido-7 ~ oxa-3-thia-l ~ asaspiro [5 «51 undec ~ l-ene (carbonyldiimidazole method)

Colorless solid with a melting point of 108-109 ° (from ethanol).

UV: Ä ^C 2 ^H 5 ^0H 220 αμ (ε 11900), 302 (35200); /! ° · ™ ^αι max 'max

228 ιημ (ε 15200), 256 (10900), 299 (22600).

IRr-O ⁰¹ '3100-3400, 1605, 1585, 1550 cm " ¹ , max

HMR: «*" ^ · ^ 12 _e 80, 8.14, "6.86, 3.97, 3.74, 3.54, 2.72, QMS

1.77, 0.96 ppm.

HS: m / e 362 (M ⁺ ), 334 (M-28), 144 (base), 111.

Analysis calculated for ^c ₁ g ⁿ ₂ 6 ^N 2 ⁰ 3 ^S: ° * ^62β9δ »7.72; S, 8.98.

W 7 T * \ 3 PR / 1

-.,, .O, *, a. ^ R Found! C, 63.06 ;. H, 7.30; N,

309809/1183

'56

HO

Colorless mail fabric with a melting point of 173.5 175 ° (from ethanol).

UV: j; ^C 2 ⁿ 5 ^OH 257 mn (c 12000), 292 (27250)? Λ ° '- ^miC1 max .max

220 m | i (ε 9300), 267 (23150).

Max

'i ^' ¹ I 8.05, 7.27, 3.78, 3.78, 3 »60, 2.74, 2.38, 1.80 ppm.

MS: m / e 304 (M ⁺ ), 276 (M-28), 144, 11.9 (base), St.

Analysis calculated for ■ ° ₁ 6 ^Η 2ο ^Ν 2 '° 2 ⁸ " ^{ί Cf 65 # i! Ä} i ^H » ⁶ * ⁶ 3 »Ii, 9» 21f S, 10.55; found: C, 63.42; 1, 6.57; N,

9.42; 3, 10:51.

Colorless peütstoff with a fine SöliÄelfcptölitt * ön 94,5-95,5 ° (aka ethanol).

UV: A ^C 2 ^H 5 ^OH 225 µ (c 6300), 2.38 (6900), 065 (16000); Max

226 πιμ (ε 11620), 247 (12750).

_IR . _o KBr 3! 00-3400, 1740, 1555 em " ¹ .

Max

TDm

TMR: J ^X 3 3.66, 3.48, 2.68, 1.50-2.34 ppm., TMS

MS: m / e 300 (M ⁺ ), 272 (M-28), 144, 111 (base). Analysis calculated for ^Ii ° ₁ 3 2o ^N 2 ° 4 ^{S: Cf} - ⁵ 1.90; H, 6.71; N, 9.33; S, 10.67; Found: C, 51.98; H, 6.96; K,

_r 309809/1183

BADORtOINAL

~ 57 -

2241 HO

9.16; ' 'S, 10.83.

[ 51 ^ lundqo-l · "- ^ !! (Bäro? Echlprid ^; Meth_qcle j

Colorless solid with a melting point of 182.5-184 ° (made of! ethanol).

• Π H OTT Or ₇ S- ',, h5-, _nr , \ rO, lMCl " ₀ ", / _,, "* ΛΛ \

UV: Λ

Max . Max

254 (14300).

cm * " ¹ .

Max

^ ⁰³³⁰ p

NMR: ^ ⁰³³⁰ S 12.20, 7.23, 3.80, 3.57, 2.80, 1.82 ppm. TMS

MS: m / e 359 (M ⁺ ), 330 (M-28), 293, 173, 144, 111 (basis) Analysis calculated for C ₁₅ II gCl 1 OgS: C, 50.19; H, 4.49;

N, 7.80; S, .8.93; Found: C, 50.31; H, 4.57; N,

7.78; S, 8.93.

η) Rac. 2-o-meth? ₁ rlbenzamido ~ 7-oxa ~ 3 - thia - l - azaspiro [^ 5-l undec-1-en (acid chloride method e),

Colorless solid with a melting point of 82-83 ° (from ethanol).

UV: λ 2 ° ^Η 5 ^ΟΗ κμ 250 (ε 10600), 281 (20400); I ° - ^imicl max max

256 mμ (ε 20650). '

IR: O ^KBr 3100-3400, 1605, 1590, 1560 cm " ¹ .

Max . ■ ■ -

NMR: <f ^{CDC! 1} 3 12.25, 7.88, 7.24, 3.77, 3.52, 2.75, 2.58,

TMS 1.79 ppm.

MS: m / e 304 (M ⁺ ), 276 (M-28), 144, 111 (base).

309809/1183

BADORfGlNAL

2241U0

Analyco Ixrr ^ hnet for 0. _V H_ _r H _o n_.Si 0, 55.71? H ₁ = 5 75; , 10.00; S, 11.44; '11! "

_Γρ 1 _3Γ 1 ..!., -, _r ., .- ,,,., _{Tr r} - ₇ , -. _{T. T} 10.02; S, 11:52.

⁰ ) I! Ao, 2 · -_ (^ - Purpamido) -7-pxa - ^ - thifi-l-ayf-Bρ1τ · οΓ 5, 5 '\ /■-vivaP.o

Painless solid with a Schmslapui> kt of 101-103 ° (from ethanol).

υν: Χ ^Ο 2 ^Π 5 ^ΟΠ 260 ΐημ (ε 9900), 303 (3,000); X ^{0 # liiiIC1} max max

235 πιμ (ε 8800), 258 (10600), 291 (25ΒΟΟ).

IR: O ¹ ^ ¹ "3100-3400, 1610, 1555 cm" ¹ , max

ρ rim
S °; 5 l? .4O, 7.55, 7.23, 6.5 ?, 3.75, 3.58, 2.67,

1.78 ppm.

. MS: m / e 280 (M ⁺ ), 252 (M-28), 144, 111 (base), 95.

Analysis calculated for C II ^ O ί! Ί C, 55.71; H, 5 = 75; N, 10.00; S, 11.44; Found: C, 56.00; II, 5.75; N,

10.02; S, 11:52.

ρ) Rao. 2- (2 ~ Th cmoainido) -7-oxa-3 ~ thia-1-agas p irp [ ^l ) ₁ 5lundec- 1-en (Carbony ldiim idazo.l-Mn bhode)

Colorless Festatoff with a melting point of 115-116 ° (from Aothanol).

UV: A ^C 2 ^H 5 ^0H 262 ΐημ (ε 12700), 271 (11700), 307 (26200), max

^OtlfflC1 274 ομ (ε 15000), 298 (15800).

Max

3100-3400, 1575, 1560, 1520 cm * " ¹ .

30 9 809/1183 -

mi CVUi _BAD ORIGINAL

ΤΠ3 1.77 ppm.

224IUO

12.50, 7 = 82, 7.49, 7.05, 3.75, 3.57. 2.75 ".

MSi ra / e 296 (H ⁺ ), 268 (Ιί-28), 144, 111 (base).

Analyt-G bojoohnot l'ür 0 Jl ^ N ₂ OgS ₀ : C _f 52.70 ;. H, 5.44; N, 9.46; S, ^ 1.6; ^ Found: C, 52.41? ^H »5.58; N, 9.44; S, 21.32.

Parblosor solid with a Sclimolzpimlrfc of 124.5-125.5 ° (from Aothsnol).

UY: X ^C 2 ⁿ 5 ^OH 235 κµ (c 7350), 258 (17200); / ° < ^miö1 max max

227 (12950), 246 (11200).

IR: ^< 0 ^KBr 3100-3400, 1585, 1560 om " ^1st max.

^^ -'- 3 3 _{# 67i 5 #} 4o _f 2.70, 1.73f 1.17 ppm.

Analysis bereolinet for Ö.JIgpHgOgS-: C, 57.75; H, 8.20; H, 10.36; S, 1.1.86; Found: G, 57.50; H, 8.24; N-,

10.31; S, 11.71.

^r ) ^ _r ^

"uncicc-l-en (ΰοΛ

Light yellow solid with a melting point of 126 ~ 127 ^O

Analysis calculated for C IL IT ^ O.S: C, 53.72; H, 5.11; N, 12.53; -S, 9.56; Found: 0. -53.87; H, 5.07; II, 12.70; S, 9.73.

509809/1183

BATH ORIGINAL

2241U0

Yellow solid with a fjclunit point of 164.13 ~ X65 _f 5 °.

Analysis calculated for C__li _2v N..O _2: C, 61.23; H _r C. 95; N, 12.60; S, 9.62; Found: C, 61.29; H, G.09; H,

12.76; H, - 9.87.

) R ^ c ^ j-rriJ- ^ faPJli ^

Colorless feather with a melting point of 133.5-140.5 °.

Analysis calculated for ^c ₁ q ^h ₂ o ^N 2 ° 2 ^{S: Cf 67} · ° 5 » ^H * 5.92; N, 8.23; S, 9.42; Found: C, 67.34; H, 5.92; N, 8.23; S, 9.29.

^u ) Rac. 1 - (2.4 ~ dichlorobenzamido) -7 | oxa-3-thia-l ~ azaapir o [5, 5 ~ lundec-l ~ one (acid chloride method) _i

Colorless featatoff with a melting point of 83-89.5 °.

Analysis calculated for ^C ₁ 5 ^H ₁ 6 ^C1 2 ^N 2 ° 2 ^{S: G | 50} ' ¹⁵ ' ^H » ⁴ * ^ 9; N, 7.80; S, 8.92; Found: C, 50.12; H, 4.49; N, 7.83; S, 8.93.

v) Rac. 2- (4-Phenylbenzamido) -7-oya ~ ^ ~ thia-l ~ aza s piro [5 «^ 1 undec ~ l ~ en (carbonyldiimidazole method)

Colorless solid with a melting point of 147-148 °.

Analysis calculated for C ₂₁ H ₂ N ₂ O ₂ S: C, 68.83; H, 6.05; N, 7.64; S, 8.75; Found: C, 69.03; H, 6.05; N,

7.671 S, 8.73.

309809/1183

~ 61 -

2241HÖ

Colorless solid mil · cdiism Böhme Izpmjkt of 102> 5 ~

Analysis calculated for C ^ jLJLQgSi 0, 57 »71 j Η» 5 »n8_j Π, 14.42; S, ll.OOj ÖefüMehi Ö, 57 * 96 * H, 5 * 89 * N,

A mixture of 0.8 g (4.3 mmol) of 6-ethylamine. 6-hexan-4-one-l-ol, 33 g (4.3 mmol) of silicone substance, 13/5 ml of toluene and 4 * 3 ml Glacial acetic acid wifd untöi * Eüiiien 3 ötundöia lang pin RüokflUöS heated »The solution obtained is divided into? evaporated vöimindertöta pressure and the Eindampfrüokstand is cooled and a UefeerschUss Einei ^4! Oxigen aqueous Natriumh ^ droxydlösung treated. The alkaline (Roman) is extracted several times with methyl chloride. The extracts are combined, washed with sodium chloride solution, dried, filtered and evaporated under reduced pressure, 0.4 g of a pale yellow crystalline residue being obtained rac, S-Amino-t'-oxä - ^ - thiä ^ l-azaspiro [5,53undec-l * -en in the form of a yellow solid with a sharp point of 143-145 ^ö «

The starting material used here can be as follows being held:

A solution, cooled in an ice bath, of 16.1 g (0 * 13 mol) of crude 1-hexene ^ 3,6 "diol, 530 rol l, 2 * dichiöräbhan (dried over anhydrous potassium carbonate), and 80 ml (56.2 g, 0.77 mol) diethylamine, 154 g of activated manganese dioxide are added in portions with vigorous stirring. The mixture is 1 hour

309808/1 18 3

BADORLGiNAL

lang hoi 0-5 ^υ and h.iorruf. 1.8 Stuwdon long at Haunt eirpora'trugt stirs.

The mixture is filtered and dor Filterrückato.nd grand ·· borrowed by inehrraaligof .; AuföchläiMuicm washed in frirjcheiii DieHloratban »Dac Filtrat and the tfaijefrvraoner Wux-den voroinigt and under reduced pressure oinedruipft, whereby 22.7 β of a red Oeleo served up»

This oil is mixed with 150 ml of ethyl acetate and 500 ml treated with a 1.2N aqueous hydrochloric acid »After vigorous Shake the watery Phäüe separated and three times with 150 ml each of ethyl acetate extracted *

The aqueous acidic solution is made alkaline with 100 l of an ION aqueous sodium hydroxide solution (pH 12) and extracted four times with 150 ml of benzene each time. The Bena oil extracts are combined and washed twice with 50 ml of sodium chloride solution, dried and evaporated under reduced pressure, wobej. 10.2 g of the Mannich base 6 ~ DläthylaDiino-hexcm-4 ^ka 0n ^ -l-ol are obtained in the form of a yellow oil; (Alternative designation 2 *. (2 ** Diä'thylamino " ^k äthyl) -

, 1715

Max

NMHi 5 ^C11C1 3 5.17, 3 * 87 | 2.62, 1 * 87, 1 * 07 ppm »MSi m / e 18? (M ⁺ ), 172 (M-15) »

Solution tön roheia ιι§ |> ΐ6ϋ * 6 * »Θη * 5 * οιι-1 * οΐ (7.9 tnMoi), 0.6 g (7 # 9 mmOl) thiourea and 7 ml of glacial acetic acid is made at room temperature 18.5 hours and then evaporated under reduced pressure at 55 ° * Dei Bindämpfriickötahd wifd

309809/1183

BATH ORIGINAL

224 1UO

treated with Acthcrü and twice with 10 ml of an IF uorscirjgeri Snlü-iiliurc extracted. The se.urüii extracts have been combined and a with Aether gov-.f.ocherij wit one! Above aqueous Katriurehydroryd-Ib " solution made alkaline and saturated with SaIs.

The alkaline'G-eKisseli is extracted three times with methylene chloride * The combined Ilöthylenchlkridextrakte are dried (VigttQ.), Filtered and evaporated under pressure, whereby 0.85 g of yellow, crystalline rac, 2-amino-7 ~ oxa ~ 3 -thia-l-asaöpiro [ 5> 5] undec-l ~ cn receives. By Uraltriijtallisation cub ethanol you get light yellow crystals with a melting point of 136-139 ° *

The raw material used here can be as follows
will be obtained:

A mixture of 25.2 g (0.122 hol) of crude ethyl 7-chloro-5-oxoheptanoate, 15.5 g (0.25 mol) of ethylene glycol, 0.25 g
p-Toluenesulfonic acid moiety and 200 ml of benzene are refluxed for 5 hours while stirring. The resulting mixture
is cooled and a saturated aqueous sodium bicarbonate solution is added in excess. The benzene layer will
removed and the aqueous layer is extracted twice with ether. The organic solutions are combined over
Sodium sulphate, dried, filtered and evaporated under reduced pressure, 29.4 g of 7-chloro-5-oxoheptanoate-ethylene ketal being obtained in the form of an orange oil, which without further
Cleaning is processed further,

IR, O

A mixture of 5.7 grams (0.15 moles) of lithium aluminum urohydride
and 300 ml of anhydrous ether is stirred in a ftisbad, while a solution of the crude 7-0chloro-5-oxoheptanoate-ethylene ketal in
50 ml of ether is added dropwise over 20 minutes,

309809/1183

BADORIQtNAL

22A1H0

YifAu; Entfciuung de υ JJisbaden viva das ei-haltono fraug .- 'Unc Geminch at low temperature for 5 Stumlon stirred, whereupon vicder carefully and dropwise under cooling '11, (5 ial water and 9 ml of an 'λΟ'Μ ^ οη aqueous itatriumhydroxyülösim / j zugenet ^f -vl; werd <m,}] ici.ri? AiI \ ?: is stirred at room temperature 1.25 ntwidon, filtered and the Pi.lt rubbed and thoroughly washed with friBCbom Aother, Dan filtrate and the V / Aoch ^ 'äss are combined and evaporated under reduced pressure, where ωίΐη 2; T _t 4 g rolioH 2- (2-0h.lorMthyl) ~ 2- (4-hydroxybutyl) -l, 3-dioxolane in the form of a ge3. bcn Ool.cn receives, which is not widely gorpurified.

IR: ^ ^ 3400 cm " ¹ .

A mixture of 2 g (916 mmoles) of the above Hydroxyketalc obtained, 5 ml of J3N aqueous sulfuric acid, 15 ml V / asBer and 15 ml acetone is at room temperature for 3 hours stirred for a long time and then poured into a saturated sodium chloride solution gonsed. The organic materials are used three times Aether extracted. The ether extracts are combined, washed once with sodium chloride solution, then ge over magnesium sulfate dried, filtered and evaporated under reduced pressure, 1.3 g of 7-ChlorhGptan-5-on-l ~ ol in the form of a yellow Oeles receives. This crude material is used without further purification continued to be used.

IRi ^ ^ ¹ 3400, 1715 cm " ¹ .

The crude chloroketone thus obtained is treated with 1.2 ml of triethylamine mixed. After a few minutes, a solid begins to precipitate. The mixture is kept at room temperature for 2.5 hours and then diluted with ether. It is then filtered and with A9ther washed well. The filtrate and the wash water are combined and evaporated under reduced pressure, whereby J.05 g Η © ρ $ -6-βη-5-οη-1-ο1 in the form of a yellow oil.

309 809/1183

,; ■■; ■ '■ ^; : - ■ '■■ :, U - \.' J ■ '■

BATH ORIGINAL

.- 65 ~

IR: v ^{> Pr: Lm} 3400, 1680, 1620 cm " ¹ .

A Geniseh of crude 2 ~ (2 ^ 0hloräthyl) ~ 2 .'- (^ by ij, 3 ~ dioxolane (6.17 mmol) of _t .0, Λ7 € -C.6 _»17: mmol) thiourea ±,. ■ 6.2 ml Biseosig, Ό, 2 ml Via & sser -und _; 20 ml of toluene. Will - at Ra \ mtempeiatm '' 1.5 hours, long ^ esiitoi; ^ md liioipuf 2.75 hours ^ s heated .. The OThaltejae mixture ^ ird ^ / ui ^ ei * vex- Βΐαις? 1ΐ eingQdanipft {tmd dea? Evaporation is treated with {and two-way; .with earth thinned oil, aqueous hydrochloric acid. jüie .saur.ea Jl ^ trak ^ e '^ r ^ den cleaned _; and again with aether

ge

pit l

trookaaet, fi | Lt2? iert and i ^ nter yi & ^ jja & pz & ew. Jtei ^ cik Increase in brightness © daiÄpft, w ^ at Jiian ^ _f: ^ ^ c. ar ^ i ^ Q ^ -oxar-Sr ^ iia- ^ i ^ * 4 l ^ ec. ~

en in viFprm> © iiias yellow leatjSffeoffes * eiphalte, Rieses: MaifeeD * i.al ■ ¥ ir4 in heAs _: sem 4 © ^ haaol lot 4m _; d jnit ßjM ; g Ifele ^ Et ^ aiire -be acts. Biir ^ ^ ä ^ ajl ^^ a ^^ _s the colorless

.a

: Iiaa ihdjerbei wr ^ e ^ dB ^ A ^ isga ^ psmatearial .Jcann as follows

JitsL .Ae ^ hyle ^ gly ^ pl, 2 ^ 5 ml ^ o ^ ejitiPiierifee-r ^ h ^ f £ elsli \ pe j ^ de ^ at ^ Bgj ^ ejipejiatiytr.; ^

^^ n Jfatr ^ wpb ^ arbOjna ^^ erhaltsnq mixed will, threeiaal -with aether, e. Biß AetherextEaMjQ w.erdfii ^ ereinigib ».einmal md.t, ahloridlösvmg gewascheai, over Magnesiumauliat _; ge.tr <3i, okne-t,

^: Wed BAD0R.6INAL

filtered and. itntur vuriranderfcoin Bvuck oirryociaupxt, uo "U: i man 2.3 S raw? Fio "tl; /l-6-ch'lor-4-oxnfne.Ar: noat-ä1; hyLcnlrctn'L receives ·.

. _r "ν film.," .- -1

^CDCl ^ 5-93, 3.67 ppm.

A LptiUn ^ of 7 ml Natriuia ~ l) iii-2r-raotV, o.xyät.lKÄy "aliirn: lT} ur; · hydride (70yiigo Löauug in toluene) in 10 ml toluene - is stirred in the Kiabad, while one a solution of 2.2 g DOUE according to. obi.ßon information received roheu ketal in 10 ml iColuol tropienvioiss during X ¹ J minutes BUBetzt. 3) ie erhiiltene Löoung vrird 1.75 hours at Räumtenporatur gerülirt and Jaierauf carefully into a g ^ The mixture obtained is extracted three times with ether, whereupon the ether extracts are combined, dried over magnesium sulfate, filtered and evaporated under reduced pressure, whereby 1.2 g of crude 2- ( : 2 »chloroethyl) ^ 2 - (3 ^ hydroxy ~ propyl) -l, 3-dioxolane obtained in the form of a brown color. This material is used without further purification.

-The '.above iR

iBeiaplel 25

A solution of 1.1 g (5.5 mmol) of crude rac. 2r-AraijaQ-7-oxar-5 ~ tMa-l-azaspiro [5 _it 6] dodea-l-ene in 10 ml of pyridine is treated dropwise with 0.55 ml of benzyl chloride. Djuj Geuisch, is stirred for 5 hours at a warm temperature, then with an excess of sodium carbonate, saturated with sodium carbonate, and oxtraliated three times with ether. J) Io ether extracts are combined, waxed with Katriumphloridlöatung, over magnetium sulfate

- $ 305.80 / 1 1: ^

"" ^ BAD ORIGINAL

22Al HO

vobwi ΐαε, η l _e (> £ rae, 2 «! i3er _A :: r-.r.: ic] o ~ 7 ~ c: <£ .--- 5 ~ tliic.-l - ai: aspiroL! ! J _f G] öocio (i ~ l-cn in For. «Ciuoss Oslo. · Π get-

oi-'c 'llaterj; -. "! is chromatographed on 85 g of Silica. LluiiGrai.r j, iit Jioxiaol-Aetlier (19il) gives 0.45 S cle-ß

IT / t ^C 2 ⁿ ^ ^0H 257 m | i (ε .11720), 285 (15750), ° · ^1ΠΗ01

liüxx -. Max

258 ίαμ (ε 171'JO).

MS: m / e 304 (H ⁺ ), 2 '] G (M ~ 28), 158, 125, 105 (base).

Day used here AiTScangenifiteri.al can get as follows \. ^r

A mixture of 3 _f 04 g (0.08 Hol) lithium-alurainituahydrid and JiGO ml trochenera ether is stirred in an ice bath, whereby a solution of 5.1 ε (0.0535-.KoI) methyl-6-oxo -T-octcnoate in 40 ral ether is added dropwise over 25 minutes. The gerainoh obtained is stirred for 1 hour at 0-5 ° and then for 2 hours at room temperature. After careful dropwise addition of 6 ml of water and 4 »8 ml of a 10% aqueous solution of sodium hydroxide solution in the cold, the mixture is stirred for a further period at a constant temperature. The precipitated solids are filtered off and washed thoroughly with ether Asphalt waters are combined, dried over magnesium sulfate, filtered and evaporated under reduced pressure, giving 7.0 g of 7-oeten-1,6-diol in the form of a yellow oil, which is processed further without further purification.

J ^ ^3u 3350, 920,

30 9809/1183

BAD OBKälNAL

22A1H0

jtiA, .L ₅ 5.55-6.03, 5.12, 4.05. 3.57, 2.83. 1.43 ppm, TMS

MSr lii / e 144 (M * ¹ '), 57 (base),

A solution of the diol (7 g) obtained according to the above information, ^of 2512 ml of diethylamine and 186 ml of 1,2-dichloroethane is stirred in an egg bath while 48.7 g of activated manganese dioxya have been prepared. The resulting mixture is stirred at room temperature for 19 hours and filtered. The pIter residue is washed with methylene chloride. The piltrate and wash waters are combined and evaporated under reduced pressure.

The remaining oil is with 100 ml of a 1.2N aqueous Treated hydrochloric acid and extracted three times with ethyl acetate. The aqueous acidic solution is made alkaline with sodium hydroxide and extracted four times with benzene. The benzene extracts are combined, washed with sodium chloride solution, over Magnesium sulfate, dried, filtered and evaporated under reduced pressure, giving 2.4 g of l-diethylamino-octan ^ -one-eol in the form of an oil.

NMR: £ ^CDG1 3 3.62, 2.53, 1.47, 1.02 ppm. TMS

MS: m / e 215 (M ⁺ ), 100, 86.

A mixture of 2.4 g of the above Mannich base, 0.88 g (0.0116 mol) of thiourea, 50 ml of toluene and 17 ml of bisacetic acid is added to the back for 3 hours with stirring and water separation river heated. The resulting mixture is stirred for 16 hours at room temperature and then evaporated under reduced pressure. The viscous binding vapor residue becomes with a 10? 6 Treated aqueous sodium hydroxide solution and extracted four times with methylene chloride. The extracts are combined with

309809/1 183

22411AO

Washed sodium chloride solution, dried over magnesium sulphate, filtered and evaporated under reduced pressure, 0.25 g of rac, 2-amino-7-oxa-3-thia-l-asaspiro [5,6] dodec-l-ene in . Onea form obtained dark Oelea.

3500, 3400, 1620, 1580 cn " ¹ .

Example 26

Rac «2-p-fluorobenzamido-7-oxa-3-thia-l-azaspiro [5.4] dec-l-ene hydrochloride is obtained by reacting 7-oxa-3-thialazaspiro [5.4] dec-l-en with p-fluorobenzoyl chloride in pyridine and subsequent treatment of the oily product with hydrochloric acid. The substance obtained is a whitish pesticide with a melting point of 193-194 ° (from methanol).

UV: A ° 2 ^H 5 ^0H 247 πιμ (ε 11650), 290 (24400) max

IR: O ⁰¹¹⁰¹ S 225Ο-325Ο, 1685, 1575, 1555 cm "" ¹ , max

NMR: i ^DMS0 " ^TPA 8.30, 7.30, 4.10, 3.35, 2.35 ppm. TMS.

Analysis calculated for C ₁₄ H ₁₅ PlT ₂ O ₃ S.HCl: C, 50.83; H, 4.88; N, 8.47; S, 9.69; _Found . _Cf 50.82; H, 4.96;

N, 8.38; S, 9.74.

Example 27

The following substances are derived from rao. 2-Am ± no-> 7-oxa-3-thia-l-azaspiro [5.4] dec-l-en in analogy to the Method © described for the spirothiazine pyran series (Examples 12, 14, 16 or 18) get:

Rac. 2 »

3Ο9Θ09 / 11Θ

22A1H0

Rac. 2-Benzamido-7-oxa-3-thia-1-aza3piro [5.4] dec-rl-en.

Rac . 2-p-Bromobenzamido-7-oxa-3-thia-1-azaspiro [5 _t 4] deci-1-en.

Rao . 2-p-Methoxybenzamido-7-oxa-3-thia-l-azaepiro [5.4] dec-

Rao • 2-o-Huorbenzamido-7-oxa-3-thia-1-azaapiro [5.4] dec- 1-ene.

Rao. 2-p-chlorobenzamido-7-oxa-3-thia-l-azaepiro [5.4] dec-

Rao. 2- (1-Adamantanylcarboxamido) -7-oxa-3-tnia-1-azaspiro [5 _t 4] dec-1-en.

Rac. 2-cinnamamido-7-oxa-3-thia-1-azaspiro [5.4] dec-1-en.

Rao · 2-ethoxyacetamido-7-oxa-3-thia-1-azaspiro [5 »4] dec-1-en.

Rao. 2-Ehenylacetamldo-7-oxa-3-thla-l-azaspiro [5 »4] dec-len.

Rao · 2- (3-phenyl) ureido-7-oxa-3-thia-1-azaspiro [5.4] dec-1-ene.

Rao. 2-Phthalmido-7-cxa-3-thla-1-aza8piro [5.4] dec-1-en. Rao. 2-Ben «ylamino-7-oxa-3-thia-l-azaepiro [5» 4] dec-l-en.

Rao · 2-Jfottaylamlno-7-oxa-3-thla-1-azaaplro [5.4] dec-1-en.

Rao · 2-phenylamino-7-oxa-3-thia-1-azaspiro [5 , 4] dec-1-en.

Sao. 2- (3-Trifluoromethylbenzamldo) -7-oxa-3-thia-lasaepiro [5 »4] deo-1-βη.

Rao · 2na-Pluorben * aialdo-7-oxa-3-thia-l-azaBpiro [ 5, 4] deo-1- · η.

Rao. 2-o-Chlorbenaamldo-7-oxa-3-thia-1-azaepiro [5.4] deo-1- · η.

Rao. 2- (2 _f 4,6-Trlmethylb6nzamldo) -7-oxa-3-thla-laxaepiro [5 »4] deo-rl-ren.

Rao · 2-p-5itrobenzajaldo-7-oxa-3-thia-1-azaepiro [5 , 4] d # ol- «n.

Rao. 2- (3,4 _f 5-Tria »ethoxybenzainido) -7-oxa-3-tbJ.a-lasaepiro [5» 4] deo-1-βη.

Rao. 2- (3 f 4-dimethoxybenzamide ο) [5.4] dec-1-βη.

309809/1183

Rac. 2-p ~ CyanbenEOjn ± do-7-oxa-3-thia-l-asaspiro [5,4] dec-1-en »

Rac. 2-p-n ~ butoxybenzamido-7 ~ oxa-3-tMa ~ l-asaspiro [5.4] dee-1-en,

Rac. 2 «p ~ methylbenzainido-7-oxa-3-thia ~ l-azaspiro [ 5, 4] decl-en,

Rac. 2- (3-Carbomethoxypropionainido) -7 ~ oxa-3-thia-lazaspiro [5.4] dec-1-en.

Rac. 2- (2,6-Mchlorobenzamido) -7-oxa-3-thia-1-azaspiro [5.4] dec-l-en. ·

Rac ♦ 2-o ~ methylbenzamido-7-oxa-3-thia-l-azaspiro [5 _f 4] de c ~ 1-en.

Rac. 2- (2-Puroamido) -7-oxa-3-th ± a-l-azaspiro [5.4] decl-en.

Rac · 2- (2-thenoamido) -7-oxa-3-tMa-l-azaspiro [5.4] dpc-l-cn,

Rac. 2-trimethylacetamido-7-oxa-3-tb.ia-l-azaspiro [5, 4 ·] decl-en.

Rac. 2- (2,6-Dimethoxybenzamido) ~ 7-oxa-3-thia-1-azaspiro [5.4] dec-l-en.

Rac. 2- (1-Phenyl-1-cyclopentane-carboxamido) ~ 7-oxa-3-thia ~ l-azaspiro [5.4] dec-l-en.

Rac. 2- (1-Methyl-1-cyclohexane-carboxamido) -7-oxa-3-tMal-azaspiro [5.4] dec-1-en.

Rac »2-m-nitrobenzamido-7-oxa-3 ~ thia-1-azaspiro [5.4] decl-en.

Rac. 2- (4-Dimethylaminobenzainido) -7-oxa ~ 3-thia-1-azaspiru [5.4] dec-l-en. ■

Rac. 2- (1-l-taphthamido) -7-oxa-3-thia-1-azaspiro [5.4] dec-len.

Rac. 2- (2,4-dichlorobenzamido) -7-oxa-3-th.ia-l-azaspiro [5.4] dec-3.-en.

Rac. 2- (4-Phenylbenzamido) -7-oxa-3-thia-1-azaspiro [5.4] dec-l-en.

Rac. 2-l · Iicotinamido-7-oxa-3-thia-l-azaspiro [5.4] dec-l-ene.

309809/1183

22 A 1UO

Example '28

The following compounds are made from rac. 2-Aj-dno ~ 7-oxa-3-thia-l ~ azaspiro [5,6] dodec-l-en in analogy to the processes described for the spirothiazine pyran series (Examples 12, 14, 16 or 18) receive:

Rac * 2-acetamido-7-oxa-3-thia-l-azaspiro [5 _f 6] dodec-l-en.

Rac. 2-p-fluorobenzamido-7-oxa ~ 3-tliia-l-azaspiro | .5 »6] dodec-1-en.

Rac. 2-p-Bromobenzamido-7-oxa-3-thia-l-azaspiro [5,6] dodec-1-en. ·

Rac. 2-p-Methoxybenzamido-7-oxa-3-th.ia-l-azaspiro [5,6] dodec-1-en.

Rac. 2-o ~ Pluorbenzamido-7-oxa-3-thia-1-azaspiro [5,6] dodec ~ 1-en.

Rac. 2-p-chlorobenzamido-7-oxa-3-tl ^ ia-l-azaspiro [5,6] dodec-1-en.

Rac. 2- (1-Adamantanylcarboxamido) -7-oxa-3-thia-1-azaspiro C5,6] dodec-1-en.

Rac. 2-cinnamamido-7-oxa-3-thia-1-azaspiro [5,6] dodec-1-ene.

Rac. 2-ethoxyacetamido-7-oxa-3-thia-1-azaspiro [5,6] dodec-1-en.

Rac. 2-Phenylacetamido-7-oxa-3-thia-1-azaspiro [5,6] dodec-1-en.

Rac. 2- (3-Phenyl) ureido-7-oxa-3-thia-1-azaspiro [5,6] dodec-1-en.

Rac. 2-Phthalimido-7-oxa-3-thia-1-azaspiro [5,6] dodec-1-en.

Rac. 2-Benzylamino-7-oxa-3-thla-l-azaspiro [5,6] dodec-1-en, Rac. 2-methylamino-7-oxa-3-th ± a-l-azaspiro [5,6] dodec-1-ene.

Rac. 2-Phenylamino-7-oxa-3-thia-1-azaspiro [5,6] dodec-1-en.

Rac. 2- (3-Trifluoromethylbenzamido) -7-oxa-3-tliia-1-azaopiro [5,6] dodec-1-en.

Rac. 2-m-pluorbenzainido-7-oxa-3-thia-1-azaspiro [ 5 , 6] dodec-1-en.

309809/1183

* ι «

. - 73 -

2241 HO-

Rae. 2 ~ O "-Glilorbenzamiao-7-oxa-: 3 ⁱ -th.ia-1-azaspiro [5 _f 6] dodec-1-en.

Rac. 2 -. (2,4, δ-tri-ethylbenzamido) -7-oxa-3-thia "l-a2aopiro 5, öjdodec-l-eiii

Rac. 2 ~ p-ITitrobenzami & o ~ 7-oxa-3-thia-l-azasp ± ro [5,6] dodec ~ 1-en.

Rac. 2- (3,4 1 5 ~ Triiaethoxybenzamido) -7-oxa-3 ~ tliia-l ~ aaaspiro [5.6] dodec-1-ene.

Rac 2 ~ (3,4-dimethoxybonzainido) -7-oxa-3-t; hiai-l ~ a2iaspiro [5.6] dodcc-1-en.

Rac. 2-p-cyanobenzamido-'7-oxa ~ 3- "bhia-l ~ azaspiro [5,6] dodec-1-en.

Rac. 2-p-n-Butoxybenzaiaido-7-oxa-3-thia-l-azaspiro [5,6] dodec-1-en.

Rac. 2-p-methylbenzamido-7'-oxa-3-thia-1-azaspiro [5,6] dodec-1-ene.

Rac. 2- (3-.carbomethoxypropionaniido) -7-oxa-3 ~ tMa-l- • azaspiro [5,6] dodec-l-en.

Rac, 2- (2,6-dichlorobensamido) -7-oxa-3-tliia-1-azaspiro [5,6] dodec-1-en.

Rac. 2-o-methylbenzamido-7-oxa-3-thia-1-azaspiro [-5.6] dodec-1-ene.

Rac. 2- (2-Furoamido) -7-oxa-3-thia-1-azaspiro [5,6] dodec-1-ene.

Rac. 2- (2-Thenoamido) -7-oxa-3-tnia-l-azaspiro [5,6] dodec-

1-en.

Rac .. 2-Trimethylacetamido-7-oxa-3-thia'-1-azaspiro [5 ₁ 6] dodec-1-en.

Rac. 2- (2,6-Dimethoxybenzamido) -7-oxa-3-thia-1-azaspiro [5,6] dodec-1-en.

Rac 2- (l-phenyl-l-cyclopentsn-carboxamido) -7 ~ oxa-3-thial-azaspiro [5,6] dodec-1-en ..

Rac. 2- (1-Heth.yl-1-cycloh.exan-carbocamiäo) -7 "Oxa ~ 3-thial-azaspiro [5,6] dodec-1-en"

309809/1 111

22 A 1UO

Rac. 2-in-Nitrobenr2aiaido ~ 7-oxa ~ '5-thia-la ^ a! =! Piro [5 _f 6] dodec-1-en.

Rac. 2- (4-Dimethylaminobsn ^r /, amido) -7 ~ oxa-3-tliia-l ~ asasp: tro [5, .6] dodec-l ~ Gn.

Rao. 2- (1-Naphthamido) -7-oxa-: 5-thia-l ~ azaspiro [5,6] doaec- 1-en.

Rac. 2- (2,4-dichlorobenzamido) -7-oxa-3-thia-l-asa, ^c ! Piro [5,6] dodoc-l-en,

Rac. 2- (4-PhenylbGnaamido) ~ 7-oxa-3-thia-l-azaspiro [5,6] dodec-1-en.

Rac. 2-nicotinamido-7-oxa-3-thia-l-azaspiro [5,6] dodec-l-en, -

Example 29

The following compounds are made from rac. 2-amino-7 ~ oxa - 3-thia-l-azaspiro [5,5] undec-l-ene obtained in analogy to the process described in Example 12 or 14: '

a) Rac. 2- (2 '6-dimethoxybenzamido) -7-oxa-3-thia-lo _J 2; a3piro C, 5'5i'mdec-l-ene (acid chloride method)

Colorless pest with a melting point of 187.5-188.5 ° (after recrystallization from ethanol).

UV: A ° 2 ^H 5 ^OH 272 * μ (ε 16900); A ° ' ^im01 222 m \ x (ε 15020), max max

251 (13600), λ ⁰ '™ ⁰¹ 285 (6400). NS

_IRj0 CHCl _{3 54OO>} 3100-3400, 1695, 1600, 1580, 1550 cm " ¹ .

MR: i ^CDC1 3 7.17, 6.50, 3.80, 2.77, 170 ppm. TMS

MS: m / e 350 (M ⁺ ), 322 (M-28), 165 (base), 144, 111.

. Analysis calculated for Og ^ OS: C, 58.27; H, 6.33; N, 7.99; S, 9.15; Found: C, 58.39; H, 6.44; N,

309809/1 183

2241H0

7.72; .S, Q.22. .

b) ■ - feäpe ^ jrfl-Phj ^^^

Colorless solid with a melting point of 114-115 ° (after recrystallization from ethanol).

JViA 2 ρ cj} ωμ (ε 840Ο ;, ί |; ^ 8ο ^ 0 ;; λ

TMS

max - ^ max

215 χαμ (ε 13300), 228 (13480), 244 (13900).

IR: 0 ^KBr 3100-3400, 1585, 1550 cm * " ¹ , max

7.34, 3.66, 2.70, 1.69 ppm. MS: m / e 358 (M ⁺ ), 330 (M-28), 213, 111 (base), 91, 55.

Analysis calculated for ^e 20 ^H 26 ^K 2 ° 2 ^S: ° * ⁶ ^ ' ⁰¹ ' ^H »7.31; N, 7.81; S, 8.94; 'Pounds: C, 66.85; H, 7.23; N, 7.79; S, 8.94.

c) Rac. 2- (l-methyl-l-CΛ '^ clohexane-carboxamido) -7-oxa ~ 3-thia l-azaspiro [5.5lundec-l-ene (carbonyldiimidazole method)

Colorless solid with a melting point of 103-104 ° (after recrystallization from ethanol).

UV: / ^C 2 ^H 5 ^OH 236 µm (ε 6820), 269 (17800); Λ ⁰ * ¹ ^ ¹⁰¹ max max

228 πιμ (ε 13800), 247 (11450).

XR. O ² ^ ¹ * 3100-3400, 1590, 1560 cm " ¹ , max

mm

MR: S "3 3.74, 3.47, 2.73, 1.13, 0.90-2.40 ppm.

TMS

MS: m / e 310 (M ⁺ ), 282 (M-28), 144, 111 (base), 55.41.

309809/1183

2241H0

Analysis calculated for O ₁ Ji _ft , .U _o 0 "S: C"61.90; H. 0.44;

10 so 2 d. ■ ■ ⁹

N, 9.02; S, 10.53; Found: C, 62.22; H, £ 3.49 * H,

9.03; S, Ίο.23.

Example ol JO

A mixture of 10.1 g of rac. 2-p-fluorobenzainido-7 "oxa-3-thia ~ l ~ asaspiro [5 _f 5Jundec-1-en, 7.6 g d - (+) - Oamph.orfJu! Lfonßi-ujro and 250 ral ethanol Heated until all solids are dissolved and then concentrated under reduced pressure to a volume of about 70 ml. After standing at low temperature for 2 hours and standing at 0 ° for 16 hours, the precipitated pesticide is filtered off, washed with ethanol and dried, whereby 8.9 g of a colorless pesticide with a melting point of 149 ° -5-151 ° are obtained. After two crystallizations from inan

Ethanol receives / pure (+) ~ 2-p-pluorbenzamido-7-oxa-3-thia-lazaspiro [5,5] undoc-l-en-d - (+) - camphorsulfonic acid sala with a melting point of 149.5-151 °; [a] _D -22.61 ° (c = 0.9862 in CHCl ₅ ).

Analysis calculated for C _nc H _nr7 FU _o 0 _o SC _in IL _r 0.S: C, 55.54;

Ip 1] ί 2 IU 10 4

H, 6.15; N, 5.10; S, 11.86; _Gefundon . _{Cf 55 <66} . _{Hf 6 # 30} . _{N (} 5.19; S, 11.93.

Example 31

0.3 g of the salt obtained as described in Example 30 is shaken with saturated aqueous sodium bicarbonate solution and extracted with methylene chloride. After washing with sodium chloride solution and drying, the methylene extract is evaporated under reduced pressure, giving 0.169 g of colorless (H -) - 2-p-pluorbenzamido-7-oxa-3-thia-l-azaspiro [5.5] undec-l -en obtained with a melting point of 108.5-109.5 °; [a] _D + 36.71 ° (c, = Q ^ TJO in CIICl ₃ ). The spectral properties of this compound are essentially identical to those of the racemic ones

309809/1183

BAD ORtQINAt

224 Π 40

Shape.

Analysis calculated for Ό ^ Χ ,, ΜρΟ S: C, 58.43-; H, 5.56; Ii, 9.00; S, 10.40; Found: Q, 58.58; H, 5.69; H, 9.14; S, 10.27. ■

Sin CremiBeh iron 8.0 g rac. .2-p-E

5.5] ^ id © o ^ l-en .., 6.2 g l - (-) - Ganipne; rsulfonsätLre and 100 ml! Ethanol are heated until all solids have gone into solution, and then under reduced pressure Evaporated pressure. The evaporation residue is recrystallized from .approximately 45 ml of ethanol, 9.5 g of a colorless solid with a melting point of 148.5-150 ° being obtained. Another recrystallization from ethanol (30 ml) gives 7.2 g of (-) - 2-p ~ Fluor_i _3eH 2; amido-7-oxa-3-thia-l'-a2; aspiro [5.5] undec- l-en-l- (-) -camphorsulfonic acid salt with a melting point of 148.5-150 °; "Ealjj. + 19.57 ° C = 1.017 in GHCl").

Analysis calculated for Q ^ H ^ M ^ O ^. ^^^ O.S: G, 55.54; H, 6.15; Ii, 5.18; , S,

J}

6.4 β of the salt obtained according to the information in Example 32 is shaken with an excess of aqueous saturated sodium and the mixture is then extracted three times with methylene chloride. The methylene chloride extracts are combined, washed with cetrium chloride solution, dried, filtered and evaporated under reduced pressure, with one 3.45 g of colorless (-) - 2-p ~ fluoro "benzamido-7-oxa-3-thia-> l-azaspiro [5.5} undec-l-ene with eiiui * melting point of 109-110 ° is obtained ;

309.8 09 / iu3

22411 Ap

[oc] _D - 36.76 ° (c = 1020 in OIIC.U). The spectral properties of this substance are essentially identical to those of the racomisoheri form and dos

Analysis calculated for C JI "H10 S: C, 53.43; H, 5.56; N ₁ 9.08; S, 10.40; Pounds: _C , 53.2 ?; H ₉ 5.64; N,

9.10; S, 10.14.

Bet game 34

A solution of 1.15 g of 8-chloroetan-6-one-l ~ ol and 0.486 g Thiourea in 50 ml of acetonitrile is poured in for 17.5 hours heated to reflux. The solution is then evaporated under reduced pressure and the evaporation residue is stirred with acetone. It is then filtered, 0.38 g of the pale yellow rac. 2-Alaino-7-oxa-j5-thia ~ l-azaspiro [5, 6] dodec-1-en ~ hydrochlor: i.d receives. After recrystallization from methanol-ether one obtains a colorless solid with a melting point of 159-60 °.

Analysis calculated for C ₉ H ₁₆ N ₂ OS.HCl: C, 45.66; E, 7.24; M, 11.83; S, 13.54; Found * C, 45 * 8Q; H, 7.37; N,

11.64; 3, 1:50 pm.

The here used - iitsgangamatearial <! Ou3n 'Mxe iiolgt aziaalten' will be:

Sin Öemisch iron 42.5 ε (0.237 Hol) .Ketliy; l - 8-clilotr-S-ox: ooctanoal ;, 26.5 ml of ethyleisslyicol, 0.4 g of jJ-Toluolsutfoneaoremonöiiydrat and 490 ml of benzene is under hair and under Water pollution for 5 hours on the Hückflasa eiiiitat, fold the Ab-JEUnIeJi .idea Bo ^! Si3 £ it: ioa: ageiJiiBöfaeB Mlxä with .gösäfrfcigias * * ■ 'AEAS-engined,' liatriuiiibiGarboiiiaiiiSmoag vgewaselwaa ^ IMD xLiie ■ .'ÄSÄKige "Sasse ^■; §reir-., Times .with ether vextüahiert · Bi 9 ./organischen 'I & sujagesi v «EBd« n ver --iv ϊ gb, with .sodium chloride _{:! "- ■ tuag .. s} washed _{! F} : ibsT« aa.ser; free

BATHROOM 0RK3INAL

_ 79 -

2241 UO

Magnesium naifate dried, filtered and under reduced pressure eiiifVi'A. '^ Pi'ij "/ obei Juan 49 _f 7 G Melhyl-ß-clilor-G-oxcoctanoat tithy lenkeLaI in Por-m a?: - receives red oils *

«! '' Jim -]

IR: v ^1JJia 1745 mc ^J -.

A ijUfipoji ^ ion of A _t (> 5 g Lithiraialuminiuij' hydride in 200 rcX trockcner / i Anther is at Eiübad stirred _f vühronci reacting a ijöGiuig of 25 (0.10 Hol) dos according to oMgcn / mgaben obtained in 50 Kotais ml of dry ether tropfenv / oise välirend 30 1-n-jinute zuaetat]) NSS mixe. .lang h at 0 ~ 5 ° and stirred for 5 hours at _f 2 thereto Iiauratemporatur 30 minutes. After careful tropicalized zucata of 9 ½ hours of water and 7.4 ml of a 105% aqueous potassium hydroxide solution in an ice bath, the mixture is stirred at room temperature for 1.5 hours. The precipitated pest materials are filtered off and washed with ether. The filtrate and the Wasohvasser ήerden combined and evaporated under reduced pressure, 17.7 g of 2- (2 ~ chloroithyl) ~ 2 ~ (5-hydroxypentyl) -1, 3 ~ dioxolane in the porin of a yellow oil is obtained.

^{IR: O} rnax 5400 cm.

A solution of 2 g of the obtained according to the above Compound in 16 ml of acetone, 16 ml of v / ater and 5.4 ml of a 3N aqueous sulfuric acid is left for 3 hours at room temperature. gerülirt. After dilution with saturated sodium chloride solution the mixture is extracted four times with ether. The ether extracts are combined and poured over anhydrous magnesium sulfate dried, filtered and evaporated under reduced pressure, 1.15 g of S-chlorooctan-ö-on-l-ol are obtained.

IR: 0 ^Έχ2Λα 3400, 1715 cn "" ¹ , max

3 09809/1183

BATH ORIGINAL

22A1U0

J el

Rao c 2-Amino-8-phenyl ~ 7 ~ oxa-3-thia-l-azaspiro [5 _f 5 jundec-

*
1-en is reacted with p-bromobenzoyl chloride in the usual way. After chromatography, the two isomers of the racemic 2-p-bromobene5-; aiOido-8-phenyl-7-oxa-3-thia ~ l-azaspiro [5,5] undec-l-ene are isolated:

Isomer 1; Colorless solid with a Schüielz 126.5-127.5 °.

point of

Analysis calculated for Q fi 7 PO

₂₁₂₁₂ O ₂ S: C, 56.63; H, 4.75; Found: C, 56.62; H, 4.87; N,

6.12; S, 7.32.

Isomer 2: Colorless solid with a melting point of 157-157.5 °.

Analysis calculated for C ₂₁ H ₂₁ BrN ₂ O ₂ S: C, 56.63; H, 4.75; N, 6.29; S, 7.20; Found: C, 56.48; H, 4.70; N, 6.15; S, 7e25.

Example 36

A solution for injection of the following composition is prepared in the usual way:

Active substance:

Rac. 2-phthalimido-7-oxa-3-thia-lazaspiro [ 5.5] undec-Tl-en (micronized);

Rac. 2-p-fluorobeiizamido-7-oxa-3-thia-lazaspiro [5,5] undoc-1-en (micronized);

or Rac. 2-cinnaraamido-7-oxa-3-thia-l-

azaspiro [5.5] undec-l-ene hydrochloride

Per ml

10.0 mg

309809/1183

BAD OBKBiNAL

ITat riuraehl or id ! Tat riumcarb ο xyme thy Ic e llul ο se Benzyl alcohol sodium acetate 3ELO Eiseasig water

qs ad 9.0 mg 2.5 mg 9.0 rag 0.2 mg 0.3 mg 1.0 ml

example

In the usual way, the following tablets are used setting made:

ßac. 2-

% 3 ] undec - l-en;

Rac. 2-P-3

azaspirö [5.5 3'tndeo-l-en

or Rac * 2-Gin1iamamido-7-02 £ a-3-tMa-l ^

Corn starch hydrolyzed corn starch CaIe itüns t earat> 100 mg

2Ö2 mg
ag
20 mg

iii

f eise föigen eg ifethalts

Rac, 2-P-]

l-azaspiro [5,5 Jnnctec-l-en ..

or Rac. 2-Öinnar- .idb-7 ~ oxa-3-thlä-l *

azaspiro [ 5 ₁ 5 jundeo-l-en-hydrochloride

"· 309 ^: J 09/1183 10 mg

02 -

2241U0

Lactose corn starch Talk

Ge itamt fei; ioht

165 mg 30 mg

210 mg

Example 39-

Tablets of the following composition are produced in the usual way:

PrO _{1 1} tablet te

Active substance:

Rac. 2-phthalimido ~ 7-oxa-3 ~ thia ~ l - azaspiro [5 # 5] undec-1-en;

Rac. 2-p-pluorbenzaiitido-7 ~ oxa * -3 "thial-azaspiro [ 5.5] undec * -l-en

or Rac. 2-ginnamamido-7 ⁱ -oxa-3-thia-l *.

azaspiro [5t.5] undec-l-en ~ hyarochloride Dicalc iuiaphosphate dihydrate Mayo starch magnesium stearate 25 mg

175 mg

24 mg

1 mg

Total weight 225 mg

40

The usual capsules are as follows

Kac .. 2 * - aaaspiro [ % _t

Γ 5 :, > -50 «g

125.

309Ö09 /

BATH ORIGINAL

~ 03 ~

Cornstarch
! Talk

Go & a ro I; weight i.ol 41

2241 UO

mg

In the usual way, suppositions of the following are used Composition madeί

Per 1.3 g

guppo sito riujn

V / irlcBubotaiiz %

Rac. 2-phthalimido-7-oxa-3-thia ~ loL 5 _{ 5] undec-l ~ en;

liac. 2-p73 thia-l ~ azaspiro [5,5] undec-l-en

or Ilac. 2-Cinnariiamido-7-oxa-3-thia-1-

azaspiro [5 _f ^ 'Jundec-l-en-hydrochloride Hydrogenated coconut oil Carnauba V / achs

0.025 g

1.230 g 0.045 g

309809/1 183

BAO ORIGINAL,

Claims (1)

2241H0 Claims '. Process for the preparation of thiasin derivatives of the formula wherein R, hydrogen, lower alkyl, lower alkenyl, aryl-lower-alkyl, aryl, lower alkanoyl or benzoyl; R ₂ lower alkyl, lower alkenyl, aryl, aryl-lower-alkyl, or a group of the formula U _D in which R, lower alkyl, Phenyl, substituted phenyl, heteroaryl, naphthyl, cycloalkyl, substituted cycloalkyl, aryl-lower-alkyl, styryl or one of the groups - (CH ₂ ) -R ₁ - and NH-Rg, where R _x . lower alkoxy or lower alkoxycarbonyl, Rg lower alkyl or phenyl and m represents a number from 1 to 6; in which furthermore R 1 and Rp together form a group of one of the formulas II γ Y or ο 309809/1183 22A1U0 wherein Y is a lower alkylene group having 1 to 10 carbon atoms or an o-arylene group is; R ,, hydrogen, lower alkyl, phenyl, 3,5-Di- (lower alkyl) -isoxas5Ol-4-yi-ethyl, 4,4-lower alkylenedioxy or arylenedioxy-1-pentyl or 3-cyanopropyl and η a number means from 1 to 5, and of tautomers, enantiomers and acid addition salts of which, characterized in that one or both water atoms of the amino group of a compound of the formula replaced by a substituent IL and / or R ₂ , or that one for hearing position of a compound of the formula where R ", lower alkyl, lower alkenyl» aryl or aryl- ^{lower-alkyl, R! l} _{2 is} hydrogen, lower-alkyl, lower-alkanoyl, aryl or aryl-lower-alkyl and R, and η have the above meaning, 309809/1183 a compound of the formula 22A1U0 «RVn purple or their addition product of the formula IHb wherein X is chlorine, bromine or iodine or a ■ ρ Group of the formula _n / 7 denotes, where R ₇ and Rg, independently of one another, represent lower alkyl or together lower alkylene having 4 to 6 carbon atoms, and R, and η have the above meaning, are reacted with a suitable N-monosubstituted or N, N-disubstituted thiourea that, if desired, a mixture of enantiomers its components are split up and, if necessary, a base obtained is converted into an acid addition salt. 309809/1183 . - 87 - 2241H0 ?. Method according to spoke 1 for the production of compounds of the formula Ia 2 'η where R ^{1 is} lower alkyl, phenyl, substituted phenyl, cycloalkyl, substituted cycloalkyl, naphthyl, heteroaryl, aryl-lower-alkyl, styryl or the group - (CIIp) -Rir, where R (- is lower alkoxy or lower alkoxycarbonyl, and R ", m and η have the above meaning, characterized in that the amine of the formula II with an acylating agent in the presence of a base. 3. The method according to claim 1, characterized in that that the amine of the formula II is reacted with an acylating agent in the presence of a base and that the obtained Compound of the formula Ia with an alkylating agent or an acylating agent in the presence of a strong one Base implements. 309809/1183 83 - 2241H0 4. The method according to claim 1 for the preparation of compounds of the formula Ib where R-., R _fi and η have the above meaning, characterized in that the amine of the formula II is reacted with a lower alkyl isocyanate or with phenyl isocyanate. 5. The method according to any one of claims 1 to 4, characterized in that a starting material is used, wherein R 1 is hydrogen. 6. The method according to any one of claims 1 to 5 »characterized in that a starting material is used where η is the number 2. 7. The method according to any one of claims 1 to 3 »5 and 6, characterized in that a starting material is used in which R. or R · is a heteroaryi group. 8. The method according to any one of claims 1 to 3 »5 and 6, characterized in that a starting material is used in which R, or R 'is a lower alkyl group. 9. The method according to claim 1 or 2, characterized in that that one uses starting materials which provide a compound of the formula Ia in which R 'is phenyl or 309809/1183 - 09 - 2241 UO substituted phenyl. 10. The method according to claim 1 or 2, characterized in that one uses starting materials which
provide a compound of formula Ia wherein R ¹ . in m- or p-position is monosubstituted phenyl. 11. The method according to einsm of claims 1 to 4, characterized in that starting materials are used which 2-p-fluorobenzamido-7-oxa-3-thia-l-azaspiro [5.5] undec-l-en '
deliver. 12. The method according to any one of claims 1 to 4, characterized in that starting materials are used which 2-p-Me thylbenzamido - ^ - oxa ^ -thia-1-azaspir ο [5 · 5] and e cl-en
deliver. 13. The method according to any one of claims 1 to 4, characterized in that starting materials are used which 2 ~ p-cyanobenzamido-7-oxa-3-thia-1-azaspiro [5.5] unde cl-en
deliver. 14. The method according to any one of claims 1 to 4 »characterized in that starting materials are used which are 2-p-nitrobenzamido-7-oxa-thia-l ~ azaspiro [5.5] undec-l-en
deliver. 15. The method according to any one of claims 1 to 4 »characterized in that starting materials are used which 2-m-pluorbenzamido-7-oxa-3-thia-1-azaspiro [5.5] undec-1-en
deliver. 16. The method according to any one of claims 1 to 4 » 'characterized in that the starting materials used deliver _g which Cinnamamido ~ 7 ~ oxa-3-thia ~ l-azaspiro [5.5] un & ec-l-ene. 309809/1183 2241H0 17. The method according to any one of claims 1 to 4, characterized in that daces κι an Aucs ^ angsmatcrialien used which 2-Hithaiiiüido ~ 7-o:; a-3-thia-l - r * 2aspiro [ ¹ J. 5Jundec- l-en deliver. 309809/1183 BATH ORIGINAL -Sl- 18. Yex-felrrexi for the division of pharmaceutical preparations, characterized in that one thiazindui-rvui of the funnel wherein R _{1 is} hydrogen, lower alkyl, lower alkenyl, avyl-lower-alkyl-, aryl, lower alkanoyl or benzoyl; R ₂ lower alkyl, lower alkenyl, aryl, aryl-lower-alkyl, or a group of the formula Ϊ "in which R. lower alkyl, Phenyl, substituted phenyl, heteroaryl, Naphthyl, cycloalkyl, substituted cycloalkyl, Aryl-lower-alkyl, styryl or a of the groups - (CHp) -R, and Mi-Rg means where Rj- lower alkoxy or lower alkoxycarbonyl, Rg is lower alkyl or phenyl and m is a number from 1 to 6; wherein furthermore R, and R_ together a group one of the formulas V V or J -γ wherein Y "is a lower alkylene group of 1 to Is carbon atoms or an o-arylene group; R- hydrogen, lower alkyl, phenyl, " 30 9809/1183 22A1U0 3,5-di- (lower alkyl) -isoxazol ~ 4-yl ~ ät} iyl, 4,4-lower alkylenedioxy- or arylenedioxy-1-peutyl or 3-cyanopropyl and η a number means from 1 to 3, or a tautomer, enantiomer or a pharmaceutical contractual salt thereof mixed with a pharmaceutically acceptable carrier. 309809/1 183 19. Pharmaceutical © α preparation, characterized, that it is a thiaaine derivative of the formula wherein R, hydrogen, lower alkyl, lower alkenyl, aryl-lower-alkyl, aryl, lower alkanoyl or benzoyl; R ₂ lower alkyl, lower alkenyl, aryl. Aryl-lower-alkyl, or a group of the formula ü _R wherein R. lower alkyl, / Phenyl, substituted phenyl, heteroaryl, naphthyl, cycloalkyl, substituted cycloalkyl, aryl-lower-alkyl, styryl or one of the groups - (GHp) -R, - and HH-R, -, where Rp. Is lower alkoxy or lower alkoxycarbonyl, Rg is lower alkyl or phenyl and m is a number TOn 1 to 6; in which furthermore R 1 and Rp together form a group of one of the formulas
O -CH -C- or wherein Y is a lower alkylene group with 1 to carbon atoms, n or an o-arylene group is; R- hydrogen, lower alkyl, phenyl, 3,5-di- (lower alkylJ-isoxazol- ^ yl ^ äthyl, 4,4-lower alkylenedioxy or arylenedioxy 309309/1181 22A1H0 l-pentyl odor 2-oyonopropyl \ τνΛ η a number from 1 to 3 "means or ain Tautorncroa, Enantiomeres or a pliQ.raaz6iiti & ch compatible acid addition salt heave susam / rien rait contains a phannaseiiticcli compatible carrier. 309809/1 183 2o. Thiamine derivatives of the formula R, wherein R, hydrogen, lower alkyl, lower alkenyl, aryl-lower-alkyl, aryl, lower alkanoyl or benzoyl; Rp- lower alkyl, lower alkenyl, aryl, aryl-lower-alkyl, or a group of the formula ü _Ώ wherein R, lower alkyl, Phenyl, substituted phenyl, heteroaryl, kaphthyl, cycloalkyl, substituted cycloalkyl, aryl-lower-alkyl, styryl or one of the groups - (CHp) -R ₁ - and NH-Rg, where R (- lower alkoxy or- lower alkoxycarbonyl, R ^ lower alkyl or phenyl and m represents a number from 1 to 6, in which furthermore R 1 and R ₂ 'together are a group of one of the formulas'. 0 - Y Y y ■. - / ° ^äsr O O wherein Y is a lower alkylene group having 1 to 10 carbon atoms or an o-arylene group is; R, hydrogen, lower alkyl, phenyl, 3,5-di- (lower alkyl) -isQxazol-4-yl-ethyl, 4,4-lower alkylenedioxy or arylenedioxy 309809/1183 2241 UO 1-pentyl or 3-cyanopropyl and η is a number from 1 to 3 3,
and heave tautomers, enantiomers and acid addition salts. 2 1. Thiamine derivatives according to claim 2Oy of Eorael where R ". ^{lower alkyl, lower alkenyl, aryl or aryl-lower alkyl, R 1} ^ hydrogen, lower alkyl, lower alkenyl, aryl or aryl-lower alkyl, R ~ hydrogen, lower alkyl, phenyl, 3,5-di (lower alkyl) isoxazol-4-ylethyl; 4,4-lower alkylenediozy- or arylenediozy-1-pentyl or 3-cyanopropyl, and η denotes a number from 1 to 3, and tautomers, enantiomers and acid addition salts thereof. 22. Thiazine derivatives according to claim 2o, _{# of} the formula HO Il Yes where R 'is lower alkyl, phenyl, substituted phenyl, cycloalkyl, substituted cyoloalkyl, Maphthyl, heteroaryl, aryl-lower-alkyl, styryl 309809/1183 - 97 - ' 2241UQ or the group - (GIL) _m - ^R r is, where R _{r is} lower alkoxy or lower alkoxycarbonyl, and H ₇ , m and η have the above meaning,
and tautomers, enantiomers, and acid addition salts thereof. 23. Thiamine derivatives according to claim 20, H 0 where R ,, R _£ and η have the above meaning. 24 ... thiazine derivatives according to one of claims 20 to 23 » wherein R is hydrogen. 25th Thiazine derivatives according to any one of claims 20 to 24, where η is the number 2. · 26 ..! Dhiazine derivatives according to claim 201 wherein R ^, a Means heteroaryl group. 27. Thiazine derivatives according to claim 20, wherein R. a means lower alfcyl group. ' 2 * 8 '.. thiazine derivatives according to claim 22, wherein R ¹ . Phenyl or substituted. Means phenyl. 29 ,. Thiazine derivatives according to claim 22, wherein R *. in m- or p-position is monosubstituted phenyl, 309809/1183. - O ₈ _ 22A1H0 3Q A thia ^ indcrivcit according to claim 20, of course [5.5] ün; lec ~ -I-cn. 31. A thiafine derivative according to claim 20, namely 2-pI> ethylbenzamido-7-oxa-3-thia-1-aza spiro [5.5] undec-1-cn. 32. A thiazine derivative according to claim 20, namely 2-p-cyano-benzamido-7-oxa-3-thia-1-azaspiro [5.5 33. A thiazine derivative according to claim 20, namely 2-p-nitrobenzamido-7-oxa-3-thia-1-azaspiro [5 .5] ande cl-en. 3'4, Sin thiazine derivative according to claim 20 »namely 2-m-fluorobenzamido-7-oxa-3-thia-l-azaspiro [5.5] undec-l-en. 35. Am thiazine derivative according to claim 20, namely Cinnamamido-7-oxa-3-thia-1-azaspiro [5.5] undec-1-en. 36, A thiazine derivative according to claim 20 which is 2-phthalimido-7-oxa-3-thia-1-azaspiro [5.5] undec-1-ene . I.
309809/1183