DE1809234A1 - 7-heterocyclocodids and morphids - Google Patents

Description

DR. I. M. MAAS DR. W. θ. PFEIFFER

MONCHIH Il JMItIKiTIAStI * »

Ameriean Qyanamld Companyj Wayne ^ New, Jersey _Λ V.St «A.

7 *> £ tetero3ycloeodide

The invention relates to new substituted 7-Heteroö ^ clo-7aS-dihydro ^ ö - (hydroaqr ^ odei' -raethoxy) -6, ϊΛ = endoCätheno = or -ethano) codidfe imd »tnorphide and processes for their preparation. The new compounds according to the invention can be represented by the following general formula:

09833 / U34

8AD ORIGINAL

R ₁ denotes hydrogen, a lower alkyl radical or lower alkanoyl radical, R _g denotes hydrogen, a cyang group, a propart radical, lower alkyl radical, phenyl-lower alkyl radical, lower alkenyl radical or lower cycloalkyl radical, FL hydrogen or a methyl radical “Y” Etheno- or Athano ^ ruppe and Q the Öruppe

(A)

where Rh Wasaersfeoff ούην is an alkyl radical of 1 to 7 carbon atoms and Z is the group = sJ {Rk) -N =, -0 «= N». or ° N »C (NH ₂ ) -N =», where R ^ represents hydrogen, a lower alkyl radical, .Phenylrea, halophenyl radical, lower alkylphenyl radical, lower / ukoxyphenyl radical, trifluoromethylphenyl radical, pyridyl radical, quinolyl radical, benzothiaolyl radical, dimethylpyriRiid ^ l radical or dimethyl = S'triazinyl radical. Suitable low alkyl radicals, lower alkoxy radicals and lower alkane radicals for the purposes according to the invention are those with 1 to 4 carbon atoms, - e.g. B * ethyl, -xeopropyl, η butyl, methoxy, methyl, ethoxy, n = PropoMj, n = Bufco3ty, Fomiyl, Ac «tyl, - Propionyl

909833/143 *

BAD ORiUiNAL

and isobutyryl. Typical alkyl groups with 1 to 7 carbon atoms are, for example, methyl, ethyl, η-propyl, η-butyl, isocyanate, sec-hexyl and n-heptyl. Suitable lower alkenyl groups are those with up to about 6 carbon atoms, for example allyl, methallyl and di-methallyl. Suitable lower cycloalkylraethyl groups are those with k to 7 carbon atoms, for example cyolo = · propy line thy 1, cyclobutylmethyl and cyelopentylmethyl. Examples of phenyl lower alkyl radicals are benzyl, α-phenylmethyl and φ-phenylethyl. Suitable halophenyl groups are, for example, ρ-fluorophenyl, p-chlorophenyl, m-chlorophenyl, m -brojBphenyl, o-fluorophenyl, 2,5-diochlorophenyl, 2,4,6-trichlorophenyl, 3,5-dichlorophenyl, 2,6-dibroraphenyl and pentafluorophenyl. Suitable lower alkylphenyl groups are, for example, p-tolyl, m-tolyI, o "= tolyl, ρ-isopropylphenyl, ρ-isopropylphenyl, m-isobutylphenyl. Suitable lower alkoxyphenyl groups are, for example, m-methoxyphenyl, o-methoxyphenyl, m-ethoxyphenyl and p = isopropoxyphenyl. Individual examples of pyridyl residues, quinolyl residues and dimethylpyrialdyl residues are 2-pyridyl, 3-pyridyl, ^ «pyridyl, 2-quinolyl, 3-quinolyl, 4 = quinolyl, 4,6 ° dimethyl-2-pyriinidyl and 5,6-dinethyl-2 ~ pyrimldyl. It should be noted that structures (A) and (B) represent two resonance forms of the pyrlaid ring when Z denotes the group -4J-C (NH ₂ ) -A- ^ and tautoraere of the pyrazole ring when Z denotes the group -NH-N »stands.

The new compounds according to the invention are generally available as crystalline substances with characteristic melting points and absorption spectra. They are noticeably soluble in many organic solvents, for example ethanol, chloroform, benzene and ethyl acetate, but are generally insoluble in water.

909833/1434

0AD ORIGINAL

The organic bases according to the invention form acid addition salts from a number of organic and inorganic salts. Acid additlonal salts, for example, are formed by mixing the free organic base with an equivalent amount of an acid, advantageously in a neutral solvent, with acids such as sulfuric acid, phosphoric acid, hydrochloric acid. Hydrobromic acid, citric acid, lactic acid, tartaric acid, acetic acid, oleonic acid and ascorbic acid. In the context of the invention, the alkali salts, for example sodium and potassium salts, of the free organic bases are also suitable if R ₁ in the general formula given above is hydrogen. For the purposes according to the invention, the free organic bases are equivalent to their acid addition salts and alkali salts.

The new substituted 7-heterooyclo-7,8-dihy «aro-6- (hydr oxy- or -« * thoxy) -6, 14-endo (etheno-or-ethano) ■ -oodides and -morphs (IA) and (IB) after the invention let sloh easily by treating one accordingly substituted 7- (2-formyl-1-eJLkoxyvinyl) derlvat8 (II) with a reagent producing a heterocyclic radical according to the following reaction topic

909833/1434

SAD ORiGJNAl.

909833/1 «34 _z ^ \. _{Rj (}

In the above reaction scheme, R ^, Rg, IU, B ^ * Z and Y are as defined above and Rg means? a lower alkylreat. According to this process, a suitably substituted 7 ^ i (lower alkoxy) methyl7derivet (IV), dm «^ as described in Belgian patent specification 71 * 3 * 9, is obtainable, treated with a formylating agent and then hydrolyzed and the substances (II) are directly isolated. Alternatively, a suitably substituted 7 »(1» alkoxy ~ l ~ alken-l ~ yl) derivative (III), 6 * e, as described in the known Dutch patent application 68.05648, can be obtained by fornylation and hydrolysis into the intermediate (II) transferred i © yden. In the case of the dieter AusfUhrungsforat 7 ~ (1-alkoxy-1-alken-l-yl) derivatt (III) ^ e may according to circumstances be isolated and purified or "in situ produced ¹ 'and formylated without isolation or purification *

The formylating agent is obtained by reacting a substituted formamide, for example N, N = Dlraethylforroaaid, Ν, Ν-diethylformamide, N-pormylpiperidine, N-formylmorpholine or N-methylformnilide, with phosgene, phosphoryl chloride or thionyl chloride in an inert solvent such as methylene chloride, xthylene hollow or chloroform ^ prepares. Alternatively, an excess of the substituted formamide can be used as the solvent. The fornylation reaction (IV— * II or III— => II) is also most conveniently carried out in an inert solvent, for example methylene chloride, ethylene chloride, chloroform or an upper shell of the substituted formamides used to prepare the formylating agent. The Temperaturbe "rich for Formyllerungsreaktlon is about 0 to 25 ⁰ C, in room temperature, however, is preferred. The hydrolysis can be carried out with dilute acid or dilute alkali, but preferably water

909833 / U34

> ^: «8AD ORIGINAL

get sodium actate used. When the actlion has practically ended, for which some usually do Minutes up to several hours or more are required * the reaction deletion will take a few minutes to "honor" For hours at room temperature bit aqueous water acetate or aqueous sodium hydroxide stirred and that Product is isolated. It can be assumed that the fornylation reaction described above a Poraylierungsmittelel runs, such as whether for example Compound (V) is shown, which arises from N, N-Dl »ethylforald and phosgene. This formylating agent then settles with the ketal (ZV) or enol ether (III) xu an ImlnlUHderivat (VI) as an intermediate (only shown in parts structure), the duroh Hydro * lyee is transferred to the intermediate substances (II).

R ₆ OCC-CH-M (CHj) ₂ (V) (VI)

The conversion of the 7- (2-iFormyl-1-alkoxy-yinyl) derivatives (II) into the corresponding 7-heterooyolo-7,8 "-dihydro-6- (hy <irQxy-o <ler-ethoxy) -6, 14-endo- (etheno- or ethano) -oodlde and -eorphid (IA) and (IB) according to the invention can easily be done through the treatment of an appropriately substituted 7- (2-pornyl-l- * alkoxyvinyl) derivative (II) an agent such as hydrazine, a substituted hydrazine of the formula RcNHNHg jatt hydroxylamine or ouanidine. The choice of the reagent that forms a heterocyclic radical and the appropriate condensation conditions then determine the isonic content of the product as (IA) or (IB)

909833/1434

set. For example, if hydrazine is the agent forming a heterocyclic ring, the products are (IA) and (IB), in which Z denotes the group -NH-N-, are tautoners of the pyrazole ring. These are tautomers themselves usually inseparable and the tautomeric structure of a single product in crystal form or in solution is characterized by determines the special properties of the respective connection. Physical methods such as IR spectra, nuclear magnetic resonance can be used to determine tautonic structures. Spectra and UV spectra as well as crystallographic X-ray analysis can be used to advantage.

If the reagent forming a heterocycle is a substituted hydrazine (ReNHKH ₂ ) or hydroxylamine is the products (IA) and (IB) in which Z denotes the group -H (Rc) -W- or -O = N " , Pyrasole or oxazole ring isomers which exist individually and can be separated from one another as products with distinct and different properties. Which isomer is formed in a condensation reaction depends on the respective condensation conditions (solvent, temperature and the like) and the respective condensation agent (substituted hydrazine or hydroxylamine). The products of these condensation reactions can consist of one or the other isomer (IA or IB) in a practically pure state or of a mixture of the two isomers. Separation and purification processes known to the person skilled in the art, for example extraction, fractional crystallization, ohromatographic separation and purification, can then be used to isolate the individual isomers (IA and IB). In order to determine the isomer structure of individual condensation products (IA or IB), physical methods, including in particular nuclear magnetic resonance and ultraviolet spectra, are suitable.

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SAD ORIGINAL

When guanidine is the reagent which forms a hete'ocyolua 1st, then the structures (IA) and (IB), where Z the group = N = C (NHg) = N = means two resonance forms of the pyriinidine ring.

This Kondexiaatlutisreakslonen contact üwiiökmäßig In Lc3 ~ sungsmitteln such as acetic acid, dilute hydrochloric acid, ethanol, propanol and the like. Performed ο The temperatures employed range from oäwa 50 to "TVyes 125 ° C, wototi a range of 80 to 125 ⁰ O is preferred. The reaction is carried out twice by heating in the steam bath or to the return temperature of the oil and is practically complete in about one hour to several hours or more. The new products according to the invention; are then isolated and solubilized by customary methods.

A special embodiment of the new process

of the invention (II> IA or IB) is represented by the following

Reaction scheme shown:

909833 / U34

•. BATH ORIGINAL

CH ₃ CT Sf _(IIA )

CH ₅ OC-CH-CHO

909833/1434

180923A

Sarin are R ₁ * Rg, R ₅ and Y as defined above. In this method, a suitably substituted 7- (2-Fonqrl-1HBetho * yvinyl) derivative (IIA) is condensed in a hydrazine derivative RJiHREg. The condensation products are the isomers (IC) or (ID), which can be isolated in a practically pure form or obtained as a mole and can be separated using known processes. The nuclear magnetic resonance spectra and ultraviolet spectra of these bonds allow clear structural assignments for these fyrazole isomers. For example, an isomer pair obtained by condensation with phenylhydrazine is explained by the formulas (VII) and (VIII) given below (shown only in partial structures) which correspond to (IC) and (10), respectively.

(▼ ID (TOI)

The nuclear magnetic resonance spectra and UV spectra of (VII) and (VIII) (R ₁ - H, R ₂ - cyclopropylnethyl, Y-Xtheno) are characteristic of the pyrazole isomers. The olefinic pyrasol protons in the nuclear magnetic resonance spectrum of (VII) (cy-H and C ^ tH, doublet at ^ 7.50 and $> 6.13 in dg-DMSO) have a coupling constant of 1.8 eps, while the coupling constant of the corresponding protons in isomers (VIII) (C ₅₁ -H and C ^ ₁ = H, doublet at & 8.25 or S 6.17 in (J ₆ -EMSO) is numerically larger (nMmlloh 2 * 5 ops) than expected. Furthermore, the N-phenyl protons appear l ° Phenyl ^ 5-pyrazolyl isomers (VII) as a sharp singlet at £ 7> 5 ^, while those of the 1-phenyl-5-pyrezoljrl-

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BATH ORIGINAL

Compound (VIII) appear as a broad multiplet at & 7.2-8.0, which indicates non-equivalence of the o, m «and o ¹ , m ¹ protons in this isomer. This suggests an unhindered ooplanar and conjugate conformation between the phenyl and pyrazole rings in (VIII). The ultraviolet spectrum of (VIII) gives further information

jOH

259 mu (£ 21, ^ 00) max

which agrees with the absorption expected for conjugated 3-substituted l = phenylpyrazzo. By doing The 5-substituted phenyl isomer (VII) hinders the bulky tetrahydrothebaine substituent corresponding to the pyrazole nitrogen is adjacent to the phenyl substituent, d ^ ese coplmare conformation, with which both the nuclear magnet The resonance spectrum as well as the ultraviolet spectrum

\ CH «OH

(ViI; ^ 242 mp (615300) * Max

Inflection «« gen godabeorptlooalnteyfereni ^ tBwpslnstlwsun.

Which isomer predominates (IC or ID ) _f can also depend on the solvents used for the condensation. If, for example, acetic acid is used for the condensation of (ItA) with substituted hydrazines, dl 1-aryl-substituted (or and!! obtain. A modified way of working, which predominantly yields the other isomer, the 1-aral-substituted (or other substituent-bearing)> ~ pyrazole compounds (ID), is follow =

909833 / U34

8AD ORIGINAL

The 7- (2 ° formyl »l = methoxyvinyl) derivative (HA) is reacted with perchloric acid in methanol. This presumably forms a keto-ketal (IX), which is shown below shown only in partial structure, as an intermediate in situ «the one without isolation with a corresponding one Arylhydrazine, e.g., phenylhydrazine, is condensed.

T T

CO-CH ₂ = CH (OCH ₅ ) g C ₆ H ₅ NHN-C-CHg- (IX) (X)

The phenylhydrazone (X), only given in partial structure, is then obtained as a crude intermediate. It is diluted without further purification by heating with Hydrochloric acid cyclized in acetic acid.

The substituted 7 = heteroeyclo-7 »8" dihydro = 6 ~ (hydroxy- or ° methoxy) -6, l4-endo (ätheno or ~ äthano) codide and <= morphids (Ia and IB) according to the invention are active Analgesics »like testing for analgesic activity according to the "cramp syndrome" test by Siegtnund et al., Proc. Soo. Exptl. Biol. Med., Vol. 95, p. 729 (1957) has been described, results in a modified form. This method is based on reducing the number of cramps after intraperitoneal injection of 1 mg phenyl-p-chlnon per kg body weight in male Swiss albino mice weighing 15 to 25 g per mouse. That Syndrome 1st by intermittent contractions of the Abdoraensj by contorting and twisting the trunk and stretching of the hind legs marked the three

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BATH

start up to five minutes after injecting the Fhaßyl-p-ohlnan ». The test compound is administered orally to groups of 2 mice each thirty minutes prior to injection of the phenyl-p-ehinone. The total number of convulsions experienced by each group of mice "is recorded for a period of three minutes" beginning 15 minutes after injection of the phenyl-p-ohinone. A compound is considered effective when it reduces the total number of convulsions in 2 test mice from a control value of about JO per pair to an Inen value of 18 or less per pair. If necessary, the results of this test with 10 pairs of mice can be used for each of the individual dosage values to determine a mean effective dose (ED ₅₀ ), which is defined as the dose which, in 50 % of the couples, has the number of powers of about 30 per couple Reduced to 18 or less per pair. For example, the following compounds according to the invention prove to be active analgesics when they are tested by this method in the oral dosage amounts as given in Table I below:

909833/1434

BATHROOM OHiGINAL

TABLE I.

co

co α » U) U)

U)

link

7α- (1-phenyl ^ 5'-pyrazolyl) -6,7,8, 14-tetrahydro-6,14-endoethenothebaine

(p-Pluorpheny1) -5-pyrazolyl7 ⁱ -6 # 7 » 8, 14-tetranydro-6, 14« endoethenothebaine

(4,6-Dinjetbyl «2« e-triazinyl) * 5 " 6,14-endoethenothebaine

7a - / T- (4,6-Dimethyl 1 «2-pyriraidinyl) -5-6,14» endoethenothebaln

7a- / T-C2-pyridyl) -5 ~ thebain

thebain

t7 »8,14-tetrahydro-8« 14 ~ tetrahydro>

-6.7 * 8, l4-tetrahydro «6,14-endoÄtheno-5-pyrazolyl7-6,7» 8, l4-tetranydpo-6, l4-endoäth »rto-5 = -pyx * azolyl7-6 _# 7» 8, l4 ^ tetrahydro-6,14-

(y endoSthenothebain

7a- (2-Amino-4Tpyrimidinyl) -6.7 * 8.14 · tetrahydro-6,14 ~ endoethenothebaine

N-Cyclopropylroethyl-7a- (5-pyrazolyl) -6,7 # 8, 14 «tetrahydr6-6, 14-endoethenonorthebaln-hydrochloride

N * ° Cyclopropylmethyl ~ 7a- (5> 18Oxazolyl) -6.7 ~ 8, 14-tetrahydro-6,14-endoetheno-Quorthebaln

ppyy7 (Py5py 6,14-endoethenonororipavine citrate

N-Cyclopropyline thy 1-7 "- (1-m-qhlorpheny 1 -5-pyr * J5Oly 1) -6,7 # 8, 14 -tetwihydro-6,14-endoethenonororipavine hydrochloride

oral dose mgAe body weight

100 200

200 200 200 200 100

200 200

25 25

0.01 0.004

In addition, the rat tail-tailing method developed by PE D'Amour and DL Smith "J. Pharmacol. Exptl. Therap., Vol. 72, p. 7 * (1941) can be used in modified fore. The compounds are administered eubcutaneously to groups of 5 rats each (generally as hydrochloride salts in 0.9% saline). Graduated doses are given to larger groups of rats. These rats are then individually exposed to a graded intensity thermal stimulus created with a point light source and a converging lens focused on the blackened end of the rat's tail. The characteristic response to this surely painful heat stimulus consists in the tail flicking away from the area of the concentrated beam of the heat source. The response time (in seconds) is measured for control groups and treated groups. The criterion for an analgesic effect is an increase in the response time compared to the control animals by about £ 100. Proven clinically active analgesics such as meperidine, codeine or morphine prove to be effective in this test. If desired, a mean effective dose (EDe ₀ ) for a 100 £ increase in response time compared to control animals can be determined from the results obtained with different graduated doses. When tested according to this method with the aid of a "high intensity" thermal stimulus which is set so that it leads to an average high response time of 3/4 to 6 seconds in untreated animals (control), these compounds show this Type of anaigetic activity, as can be seen from the respective mean effective doses given in Table II below «

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8AD OHJGINAL

TABSIXE II

VffrbirnJwic KgAg body weight 7a- (5- * isoxazolyl) -6,7,8, 14-tetrahydro-6, 14-endoetheno ~
tnebain
7a- (1-phenyl-5-pyrazolyl) -6,7,8,14 ~ tetrahydro-6,14 «
endoethenothebain
7a- / f * (p-fluorophenyl) -5-pyrazolyl7 ^ro 6,7,8,14 »tetrahydro-
6,14-endoethenothebaine
7a = ^ t- {4,6-Pime thy 1-2-s-triazinyl) «5-pyrazolya7-6 * 7 * 8.14-
tetrahydro-6,14-endoethenothebaine
7α »/ Γ- {2-pyridyl) -5-pyrazolyl7» 6,7,8,14 »tetr ⁱ ahydro- '
-6,14-endoethenothebaine
N '= cyclopropylmethyl-7a "(l" phenyl "5 ^il' PyrÄzolyl) -6,7,8, l4 °
tetrahydro-6,14-endoSthenonororipavin ° citrate
N-Cyclopropyimethyl «7 <x- (1 -« - chlorph «nyl-5-PyWUSoIyI) -
6 »1 , 8,14-tetrahydro-6,14-endoethenonororipavin-
hydrochloride approx 10
approx. 5
approx. 5
approx. 25
approx 10
0.14
0.52

Furthermore, additional routine tests known in this field can be carried out in order to determine the extent of the side effects which frequently occur with the morphine-like analgesics. These include, for example, effects such as onset and duration of effect, tolerability, reduced breathing, risk of addiction, relative effect in the case of oral and parenteral administration and inhibitory effect on the gastrointestinal system.

Other compounds according to the invention can have anaesthetic antagonistic activity when tested against a certain dose of morphine or other morphine-like agents. This antagonistic activity may be beneficial for a specific antidote to an overdose of a morphine-like agent or because of its non-narcotic analgesic effect. Experience has shown that such narcotic antagonisms, despite the fact that they generally prove to be inactive with the Kattc-nsshwanzzuck method (see above), are also able to relieve pain and that there is little or no risk of addiction (LoS. Harris and AK Piereon, J. Pharmacol. Exptl. Therap., Vol. 14?, P. 141 (1964). Analgesics with which a satisfactory pain relief is achieved without significant side effects, were particularly with regard to the Tolerance, habituation, and drug dependence of opiates sought for many years. When tested by a method similar to that described by Harris and Plerson, NHJyelopropylmefchyl ^ c ^ fö-py ^ aesoiyl) = 6.7 * 8, 14-tetrahydro ~ 6,14 ~ endoethenonorthebain, N ^ 2yeloppopylsiethyl = 7 $ c- (5 «= ^> isoxazole 1) = 6,7,8,14 = tetrahydro β, 14 = endoethenonorthebain

90 9 8 33 / U34

BATH ORIGINAL

and S-Cy ^ lopropyliiethyl-7a- (l-phenyl-5-pyrazolyl) -6.7 # 8, 14-tetrahydro-6,14-endoethenonororipavln analgetlsoh antagonistic effects when tested against morphine.

In addition, additional test methods can be used, for example, increasing the wave of tears in rats whose paws Inflamed with brewer's yeast can be carried out to reduce the anaigetic effects of the new To confirm compounds according to the invention. In some cases these compounds also show anti-inflammatory activity.

By mixing with suitable carriers or diluents, the compounds according to the invention can be used in In the form of pills, capsules, tablets, powders, solutions, suspensions and the like. For the administration of dosage units and to simplify the administration. As anaigetics, they relieve pain by direct action on the nerve centers or by reducing the conduction of excitation in the sensorial vision Nerve fibers. The new compounds according to the invention can also be used in combination with salicylates, e.g. aspirin * administered.

The new compounds according to the invention can exist in various isomeric forms, for example as stereoisomers! It is emphasized that all such isomeric forms are within the scope of the invention. For example, the codids used as starting materials contain several asymmetric carbon atoms. Furthermore, epimers are am asymmetrical center C ~ 7 possible. Therefore, in the products of the invention there is the formation of stereoisomers

909833 / U34

BAD ORKaINAL.

or epimers at C-7 possible. The nuclear magnetic Resonance spectra of these 7α- and 7fl-heterocyclo-7,8-dihydro-6- (hydrocyc or methoxy) -6, 14-endo (Ktheno- or -ethano) codes and -morphs are useful for identifying the mixtures of epimers or the pure stereoisomers, as they are from the Reaktlonsgenisohen or from later purifications and separations are particularly useful. These isomers can be separated by known methods, e.g. by fractional crystallization and distribution chromatography.

According to a recognized agreement, there is β loh a cc-substituent in the 7-position behind the plane of the paper « while a ß-Substituent is in the 7-position in front of the plane of the paper. In formula pictures this becomes usual by a —— bond for an α -sub tuent, a

■ - ■■■ bond for a p -subatituent and a

Binding to the joint representation of both sub-

stituents reproduced.

The invention is explained in more detail by the following examples, which represent preferred embodiments t '' -

example 1

production of fa- { H > - | aoxazolyi) -6 _ff f _t 8,14-tetrahydro- , ■ 6.14-endoethenothebaine

500 mg 7a- (2 ° formyl-1-methoxyvinyl) -6,7,8, 14 ° tetrahydro-6,14-endoätlienotliebainj 500 mg hydroxylamine-hydrochloride and 10 ml of acetic acid are heated on the steam bath for one hour. The reaction mixture is diluted with water

909833 / U3A

BATH ORIGINAL

eer and neutralize the solution with sodium bicarbonate.

The mixture is extracted with methylene chloride and

the extract is washed with water and dried *

The residue obtained after evaporation is made from methanol

to 430 mg (90 $) 7a> ( ^5e> Isoxazolyl) -6,7,8, l4-tetrahydro- 6, I4 ~ endöäthenothebain from P. 172 to 174 ° C recrystallized,

Example 2

Production of 7a- (5 «pyrazolyl) ^ _f 7« 8, 14-tetrahydro-6, 14 endoethenothebaln

7a «'(2-Pormyl <-l-raethoxyvinyl) -6,7,8, 14-tetrahydro-6, 14-endoethenothebaine, 60 ml acetic acid and 3 ml hydrazine hydrate are heated on the steam bath for 30 minutes. The crude product is isolated as in Example 1. After recrystallization from aqueous methanol, 2.8 g (97 %) of 7 * ~ (5-pyrazolyl) -6.7 # 8 "14 ° tetrahydro" = 6.14 -endoethenothebaine with a melting point of 120 to 122 ° C (below Foaming).

Example ft

Manufacture ; from 7tt ^c> (l ° Me th yl ° ^ ° p ^ razolyl) -6.7 ₁ .8.l4-tetrahydro-6,14-endoSthenothebaln

500 mg of 7a "(2" Pormyl-1 = methoxyvinyl) -6,7,8, 14-tetrahydro-6,14-endoSthenothebaine, 250 mg of methylhydrazine sulfate and 10 ml of acetic acid are heated on the steam bath for 30 minutes. The crude product isolated as in Example 1 is converted from aqueous methanol to 300 mg (60 £) 7a -> (1-Hethyl-5-pyrazolyl) «6,7,8,14-tetrahydr0-6,14-endoethenothebaine from P. 203 recrystallized to 205 ^{e C.}

909833/1434

BATH ORIGINAL

Example 4

Preparation: from 7 «° (L ° phenyl <; 5 ^ pjgrazolyl) -6 _a 7,8.1% tetra 'o ~ 6 ^ I4 ° endoäthenotheba ^ ng

- "■ ■ ■ -" - ■ - '■ ~ j; ^e iS

500 mg 7a- (2-formyl-l = methoxyviii! Yl) ^, 7,8, l4 - ^^ endoäthenothebain, ^;

250 mg of phenylhydrazine hydrochloride and 10 ml of acetic acid C are warmed up for a few minutes on the steam bath. The mixture is diluted with water and then neutralized with aqueous sodium carbonate. The separated product is separated by preparing a methylene chloride solution and then evaporating, dried and converted from aqueous methanol to 355 mg (60 Ji) 7a- (1-phenyl-5 = P3T2 »az ο Iy 1) = 6, 7,8,14 = t β trah jf dro-6, l4 ° endoHthenotlaebain from R 175 to 177 ° C uTicrystallized.

Production of 7α - »/ Γ

500 mg? A-C2 = -porffiyl-l-rrt®th03iyvinyl) = 6.7 »8 _# l * ° tetrahydro · - 6.14 = endoethenothebal, 195 mg p = fluorophenylhydra« in and 10 ml acetic acid become one hour the steam bath . The crude product mlvu tri © isolated in Example 1 and converted from methanol to "410 sng (70 '#) 7a ~ ^ ~ (P ~ fluorophenyl)« 5 ° pyrazolyl7 = 6, 7, 8 "14 -tetrahydro-e. ^^ endoathenothebaine from P. 211 to 215 ⁰ C recrystallized.

In game six

Herste I _- lun ^ von_ 7a ^ / f ^ i jl _? _6 ° Digiethyl ° 2 = q '° triag lnyl ) zolyl7 ~ 6.7.8.14 ° tetrahydro ° 6.l 4 ° endoethenothebaine '

- I aVtrni ^ - ^ l! ^ t-UJ-I IIIPHJJIHH * «I ■ I TiJ * H. »» ^^ Jl * IJfc ^^^ ■ »^ ap- ^ VJI * - ■ I ■ K- ^ J *» * ^^^ g l M ^ 1 »l ll! ■■ ^^

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BATH ORIGINAL

725 mg 7a- (2-pormyl ~ l ^ ethozyvinyl) -6 ~ 7,8, 14-tetrahydro-6,14-endoethenothebaine, 2K0 mg 2-hydrazino-4,6-dimethyl-s · triasln land 15 ml acetic acid Warmed up on the steam bath for 1 hour. The crude product is isolated as in Example 1. Recrystallization from ethyl acetate / h-hexane gives 500 mg (57 %) 7a- / T- (4,6-diynethyl-2-8-triazinyl) -5-pyrasoly7-6,7,8,14-tetrahydro-6 , 14-endoethenothebaine from P. 182 to 185 ^e C (used at 14O * C). .

Example 7

Production you 7tt- / T- (4 _p 6-methyl-2-: ayrla) ldlpyl) -5-17-6.7.8. ll-tetrahydro-6.14-endoäthenothepaln

1 β 7o- (2-Pormyl-lHnethoxyvlny ^ _# 7 »8 * l * rt» triliardro-6 # l4.-eridoäthenothebaine 500 mg 2- «ydraxino-l4, ^ - dieethylDyriS) idln and 20 ml acetic acid are 1 1 / 2 hours under ROokflui.

^ warmed. The crude product isolated as in Example 1 is warmed up on the steam bath with 50 ml of water to the ober You have to remove 2-4 | ydrazlno-4,6-dlmethylpyrlBldin, which is water-soluble. The Peststoff is separated and a solution in methylene chloride is dried and passed duroh a short column with Hagnesol "Maoh Blndaeipfen of the eluate and recrystallization of the ansohliefiendes Rüokstands Aoeton from / i-hexane, 6 * 70 mg (55%) 7a ^ T- (4,6-Diaethyl-2-pyrimidinyl) -5-pyrazolyl7-6 »7» 8 # 1% -tetrahydro-6,14-endoethenothebaine from P. 194 to 198 * C.

Example 6

Production of 7a- / T- (g »I ^> yrldyl) '- 5« pyrazolyl7-6.7 _P 8 ^ l4 » tetrahydro-6,14-endoethenothebaln

909833/1434

8AD ORlGJNM.

500 mg of 7a- (2-ponnyl-1-metho3 {yvlnyl) = 6,7,8, 14 ° tetrahydro-6,14-endoethenothebaln, 250 mg of 2-hydrazino-pyridln and 10 ml of Esßiga acid are added for 1 1/2 hours Return heated. The crude product is isolated as in Example 7. Recrystallization from acetone / i-hexane gives 360 mg (70 %) 7a-./T-(2-pyridyl )-5- pyrazolyl7-6,78,14-•ndoäthenotheba from P. 156 to 158 ⁰ C.

Example g

Production of 7tt ° / r-> f2Hfoinolyl) -5-pyrazolyl7 "6.7.8 ^ 14" tetrahydro-6,14-endoethenothebaln

500 mg of 7o- (2-pormyl-1-methoxyvinyl) «- 6.7 # 8, 14-tetrahydro-6,14-endoethenothebaln, 188 rag 2-hydrazino <» ohinolln and 10 ml of acetic acid are refluxed for 1 hour. The crude product is isolated as in Example 1. NaOH recrystallization from methanol to obtain 440 mg of 7α- / Γ- (2-Chinoly1) »5-pyrazoIyl7 ~ 6" 7 "8" 14 "tetrahydro-6,14" endo "äthenothebaln from P. II6 to 120 ⁰ C..

Example 10

Preparation of 7a ° A- (2-Benzthia2olyl) ° 5-pyrazolyl7-6 _f 7 . 8.l4-tetrahydro ° 6.14-endoethenothebaine

1 g of 7et- (2-pormyl-1 «« ethoxyvinyl) = 6,7,8, 14-tetrahydro-6,14-endoethenothebaine, 400 mg of 2-hydrazinobenzothiazole and 20 ml Acetic acid is refluxed for 1 hour. The crude product is isolated as in Example 1. Recrystallization from methylene chloride / methanol gives 1.1 g of 7a °

909833 / U34

SAD ORIGINAL

«/ 5" «(2« Ββηζ thiazolyl) -S-pyrazolylJ «^» 7> 8,14-tetrahydro-6,14 ~ endoethenothebaine from F.209 to 211 ^e C.

Example 11

Division of 7a "(2 ° Amino ° 4 ° pyrimidinyl) -6 _f 7.8, U-tatra hydro-6 _p 14-endoethenothebaln

1 g

endoäthenothebaine, 500 mg of guanidine carbonate and 100 ml of ethanol are refluxed for 48 hours. After cooling, the mixture is filtered and the solvent is evaporated. The residue is filtered with the addition of water. After recrystallization from aqueous methanol to obtain 700 mg (70%) 7a ° (2-Amino-4 "pyrimidinyl) <- 6,7,8, l4-tetrahydro ~ 6, l4 '= endoäthenothebain from P. 175-178 ^e C .

free play 12

Production of N- »C? Yclopropylmethyl ° 7tt '» (5 ° pyrazolyl)' ^ _J 7 _J 8, ^ "tetrahydro ^! L 4 ° endoSthenonorthebaln-hydroohlorid

2 g of N - (^ elopropylmethyl-7a ° (2-formyl-l ° methoxy-vinyl) -6, 7 * 8, l4-tetrahydro-6, l4 ° endoäthenonorthebain ° hydrochloride, 2 ml of hydrazine hydrate and 40 ml of acetic acid are added to the Steam bath heated for 50 minutes. The mixture is made with Diluted water and neutralized with powdered sodium bicarbonate. It is then extracted with methylene chloride. The extract is washed with water and dried. After evaporation of the solvent you get a rubber « like body, which is dissolved in 5 # hydrochloric acid. The solution is washed with ether. The aqueous phase

9833 / U34

8AD ORIGINAL

is neutralized with powdered sodium bicarbonate and the separated product is filtered off and kneaded. After recrystallization from Methylenoiilorid / methanol / acetone to obtain 400 mg N-Cyclopropylraethyl-7a = (5-pyrazolyl) "6,7,8, l4 ~ tetrahydro-6, 14-endoäthenonorthobaln-hydrochlorld from F" 303-305 ^e C ( Decomposition) The mother liquor is evaporated and the residue is treated with dilute hydrochloric acid and then with sodium bicarbonate as above. The deposited product is filtered off, washed with acetone and dried, whereby a further 450 mg of product from P. 302 to 305 ^e C and a total yield of 45 pounds are obtained.

example l'p

Manufacture of y-Cyelepropy3- ^ffie , ffiiylyC ^ 6 j 7, Qf 14 ° t etrahy drQ ° 6 _a I4 ° endpäthenonorthebaln

6.7 * 8 * 14 "tetrahydro -6.14" endoethenonorthebain "hydrochloride" 1 g Hydroxylaajin = hydrochloride and 20 ml acetic acid are heated for 1 hour on the steam bath. After adding water, the solution is neutralized with powdered sodium bicarbonate and with Methylene chloride extracted. The extract is washed with water and dried. After evaporation of the solvent, a gummy body remains, which is dissolved in methylene chloride. The solution is passed through a short column with magnesol. After evaporation of the eluate and recrystallization of the residue from methanol obtained one 500 mg (56 %) K = cyclopropylmethyl = 7a »(5 = ⁱ isoxazolyl) = * 6,7,8, l4-tetrahydro« 6 _p l4 »endoethenonor ° thebain from P. 144 to l46 ^e C.

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Example 14

Preparation of H-Cyolopropylmethyl-7a (5 »pyrazolyl)" · 6.7 * 8, l4 "tetrahydro-6. 14-endoRthenonororipevln

1 g of NC-lopropylmethyl-7 "- (2" formyl-methoxyl-vinyl) -6 _# 7 "8" 14-tetrahydro-6,14-endoethenonororlpavine "1 ml of hydrazine hydrate and 20 ml of acetic acid are warmed for 10 minutes on the steam bath. The mixture is diluted with water and then made alkaline with Aramonium hydroxide. The deposited product is filtered off, dried and recrystallized from acetone / n-hexane, whereby 58O ng (40 %) of N-cyclopropylethyl-7a- (5-pyrarolyl) -6-7,8,14-tetrahydro-6,14- endoäthenonororipavin receives from P »198 to 200 * C.

Example 15 Making p

6th , J _Ψ 8. 14-tetrahydro-6.l4-endo8thenonororlpavln

1 g of N-cyclopropylmethyl-7a- (2-forinyl-1-methoxyvinyl) -6.7 "8.14"tetrahydrO'6,14-endoMthenonororipavin, 1 g of hydroxylamine hydrochloride and 20 ml of acetic acid are heated on the steam bath for 1 hour . The mixture is diluted with water and then old aqueous sodium bicarbonate is neutralized. The precipitated product is extracted old methylene chloride and the extract is washed with water and dried. After evaporation of the solution, a rubber-like body is obtained which is dissolved in methylene chloride. The solution is passed through a kurr.e column with Magnesol ^R. The eluate is evaporated and the residue becomes with the addition of ether

909833/143 4 '

SAD ORiOiNAt

filtered off. After recrystallization from acetone / i-Ifexan obtained 280 mg of N-Cyelopropy! Methyl ° 7a '(5-ieoxazolyl) -6,7, 8, l4-tetrahydro-6 _J, l4-endoathenonororipavin of P 182-184 * C. A further 50 mg of product from P. 185 to 186 ° C are obtained from the mother liquor, so that an oesain thaw yield of? 5 % is achieved.

Example 16

Making yypftpy golTl) -6 m7. 8.14 -te trahydr 0-6.14 ° endoäthenonorthebalnhardrochlorld

5 β N-Gyelopropylinethyl-7a * (2-formyl ° lMnethoxyvln3rl) -6 _> 7 "8 ₍ 14" tetranydrp-6, 14-endoäthenonorthebaln ₄ 2.5 g of phenylhydrazine hydrochloride and 100 ml of acetic acid are on for> minutes The mixture is diluted with water and then made alkaline with ammonium hydroxide. The precipitated product is filtered off and dried in the form of a methylene chloride solution. The residue obtained after evaporation of the solvent is dissolved in methylene chloride and the solution is passed through a short column with magnesol After evaporation of the eluate, a rubber-like body is obtained. 500 mg of this product are dissolved in methanol and treated with an excess of 5 liters of hydrochloric acid. The solution is extracted with methylene chloride and the extract is dried and evaporated. The residue is added filtered off from acetone and converted from methanol / acetone to 250 mg of N-cyolopropylraethyl-7o- (l-phenyl-5-pyrazolyl) ° 6,7,8,14 »tetrahydro-6,14 => endoethenonorthebain-hydroc hloric! from P. 272 to 274 ⁰ C (decomp.) recrystallized. The rest of the rubber-like product

909833 / U3 ^

8AD ORIGINAL

is worked up in the same way, whereby a further 1.1 * 7 S or 1.243 g of product from P. 274 * C (decomp.) or 277 ° C (decomp.) is obtained. The total yield is 39 %.

Example 17 Preparation of N7C

zolyl ) -61 7 j 8 _f 14 "tetrahydro ~ 6 _Λ ΐ4 ^ endoäthenonororipavin

5 g N '= Qrclopropylmethyl ° 7a ^<*> (2-forrayl "' l-fnethoxyvinyl) -6,7, 8, l4-tetrahydro = 6, l4-endoäthenonororipavin, 2.5 S phenyl" hydrazlnhydrochlorid and 100 ml of acetic acid Heated for 30 minutes on the steam bath. The mixture is diluted with water and then made alkaline with ammonium hydroxide. The deposited product is filtered off and dried in the form of a methylene chloride solution, which is then evaporated to a glass-like body. A solution of this glass-like product in methylene chloride is passed through a short column of magnesol. After evaporation of the eluate, a rubber-like body is obtained which crystallizes on addition of ether and is filtered off with addition of ether, giving 2.8 g (43 %) of N => cyclopropylraethyl-7a "(1 ^e phenyl-5 ^e pyrazolyl)" 6 , 7,8, 14 '= tetrahydro «6,14-endoäthenonororipavin from P. 184 to 186 ^e C wins. UV ° Spectrum CH-OH

242 (Inflektionspunktj S 13 * 300) and 289 Max

(69,000).

A hot solution of 1.5 g of citric acid in 5 ml of ethanol becomes a hot solution of 1.5 g of the pyrazole in 15 Ethanol added. After standing for several hours, divorce 1.416 g N ~ cyelopropy! Methyl ° 7a ~ (l = ^ henyl «5 ~ pyrazolyl) = 6.7»

909 8 3 3 / U34

BAD ORlGiNAL

-8, l4 »tetrahydro-6,14-endoethenonororlpavln-cl was removed from the P. 26 ° C (decomp.). The mother liquor is heated and ether is added. A further 450 μg of product separate from the P. 217 * C (decomp.), So that an oil thaw yield of 98 % is achieved. IR »spectrum: ν KBr

/ max 2.93.3 * 85 (broad), 5.74.5 * 82 (shoulder) and 6.25 u) nuclear magnetic resonance (dg ° EMSO) & 7.50 and 6.13 (pyrazole C, tH and C ^ »~ H, doublet, ^ ι, ^ β ^ Ι, δ ops), 5.83 and 5.72 (C ₁ Q = H and C ₁₇ -H; doublet, JW ^ g ¹¹ 9 cps), 4.48 (C ₅ -H), 3.08 (CgMethoxyl), and 2.70 (»CH ₂ - of citratef 2 protons or 1 mole of citric acid per mole of thebaine derivative),

Example 18

Production of 7a ° ( ß ^g isoxazolyl) -6.7 _J e, 14 ° tetraiiydro '»6, 14' endoathen ooripavln

According to the general procedure of Example 1, 7a "( 2 ^ Wuvmy 1 = 1-methoxy viny 1) .- 6,7,8,14 = tetrahydro-6,14" endoathenooripavln with hydroxylamine hydrochloride in acetic acid to 7Ot- ( S ⁰ IsOXaZoIyI) ^ o, 7,8,14 = tetrahydro-6,14-endo = äthenooripavin implemented.

example

Production of 7a ° ( g ° Pyrazolyl '»6 _f 7 _f 8 _J l4' ° tetrahydro-6 ^ l4 · endoäthenoorIpavIn

Following the general procedure of Example 2, 7a "(2 = * Formyl ° 1 = methojqpvinyl) <= - 6.7 # 8, 14-tetrahydro" 6.14 = endoäthenoorlpavin with hydrazine hydrate In acetic acid too

909833 / U34

BATH ORIGINAL

180923 A

7o- (5-Pyr * aolyl) -6,7 »8,1 * -tetr * tiydro-6,14-« ndoKth »nooripavln unset.

Example 20

fteratstellung von ^^ gol yl) -6.7.8, l4 ~ totrahydro-6 «14-endoäthenoporlpavin

Ouroh Aoetylienmg von N-Cyolopropylmethyl-7ot- (5-isoxaj: olyl) 6,7,8, l ^ -tetrahydro-öfllij-endoäthenonororlpavln nit Aoetanhjr * drid in Pyridln receives own JJ-Acetyl-K-oyclopropylroethyl ^ a-

Example 21

Haretellun ^ iron 7a ° (5-l8oxa2ol _r vl) - »6.7.8, l4 ° t» trahydro-6.l4 '» endoäthenonorthebaln

Following the general procedure of Example 1, 7a * (2 ° formyl-1-methoxyvinyl) ~ 6,7,8,14 ° tetrahydro- * 6,14-endoethenonorthebain with hydroxylamine hydrochloride in acidic acid gives 7a ~ (5-isoxazoly1) -6 , 7, 8, 14-tetrahydro-6,14-endoKthenonor · thebaine implemented.

Example 22

Production of H "allyl""7a-(5-180xazolyl)" - 6.7 _J 8 ₎ il4 "tetrahydro"> -6.14 ° endoathenonor thebain

7a- (5-isoacazolyl) -6.7 »8,14-tetrahydro6,14« endoethenonorthebmin becomes with allyl bromide in an inert solvent to N-allyl-7a = (5 ° ieoxazolyl) -6.7 »8.14-th trahydro ° 6,14-endoäthenonorthe-

909833 / U34

SAD ORKaINAL

bain implemented.

hard work 2ft

Production of 7a "fft-IsoxazQlyl) -Ni>ropyl" 6 "7j8 _f l4 <" t · tr * "" h ydrp-6. H-endo & thenonorthebaln

7a- (5-Isoxazolyl) -6,7,8,14-tetrahydro-6,14-endoethenonorthebaine is converted with propylbrouid in an inert solvent to 7a- (5-Ieoxazolyl) -N-propyl-6,7,8 , l4-tetrahydro-6 _# l4-endoätheno <northebain implemented.

example

Preparation of 7a- (5-Igoxagolyl) ^ '- phenethyl ° 6.7j8 _c l4 »tetrahydro-6.l4-endoäthenonortheb & ln

7a- (5-isoxazolyl) «6.7 * 8, 14-tetrahydro« 6 _{t of} 14-endoethene-cmorthebain is mixed with phenethylobloride in an inert lung · »agent to 7a- (5-isoxazolyl) -N-phenätliyl-6,7 * 8,14-tetrahydro-6,14-endoKthenonorthebain implemented.

game 25

Production of? A- (5 ° lBoxazolyl) -N "(; 3-g.ethyl ~ g-buten-l-Yl) ₁ , 14 »tetrahydro» 6.14-endoethenonorthebain

7a- (5-Isoxazolyl) -6,7,8 _f l4-tetr «Lhydro-6,14 ° endoäthenonor · thebaln is with 3-methyl-2-but © nl-ylbromid in an inert solvent to 7a- (5- isoxazolyl) -M- (35-m 'thyl-2-buten-l-yl) -6,7 * 8, 14-tetrahydro-6,14-endoKthenonorthebain implemented.

90983 3/1434

SAD ORIGINAL Example vs.

Production of 7g ° (jj>"?E8Q; xazoly l) ~ N» proparffyl 76.7 * 8 * 1.4 » tetrahyd ro-6, l4rendoäthenonorthebaln

7 "- (5-Ieox * zolyl) -6,7,8,14-tetrahydro-6,14" endo8thanonorthebain is converted with propargyl bromide in an inert dissolving agent to 7a- (5-isoxazolyl) - "" "proparsyl" 6 »7.8, 14th *; rahydro 6.14-endoethenonorthebain implemented »

example 2Y

Manufacture of 7tt- (4 ° S thyl ° 5 "pyrazolyl) r6 _l 7 , 8, 14-'tetrahydrO' 6 _f 14" endoathenothebaine

Following the general procedure of Example 2, Ja ™ (2-formyl =: i ~ methoxy-1-butenyl) -6.7 »8,14-tetrahydro-6,14-endoSthenothebaine with hydrazine hydrate in acetic acid to 7a» (4- Ethyl = 5 ~ pyrazolyl) 6,7,8,14 = tetrahydro-6j14 ° endoHtheno »thebaine converted.

Example, g§

M anagement of 7 a - (^ ° l8oxa2olyl) "6,7i8 _f l4" tetrahydrp-6 _li l4 ^ endoethanothebaln

According to the general procedure of Example 1, 7a = (2-Pormy 1 - = 1 »methoxyvinyl)» 6,7,8,14-tetrahydro = 6,14 ~ endoethanothebaine with hydroxylamine hydrochloride in EeaigeKurt to 7a ^e (5-Iao3cazolyl) - 6,7,8,14-tetrahydro-6,14 = endoSthanothebain implemented.

909833 / U34

8AD

Example 29

Production of ? p- (5-Pyragolyl) ~ 6,7.8, l4 ~ tatrahydrp-6, Ifr ^ endoäthenothebaln

Following the general procedure of Example 2 7j3- (2-formyl ~ 1-methoxyvinyl) »6,7,8, 14 ~ tetrahydro« 6, 14- · endoäthenothebaln with hydrazine hydrate in acetic acid too 7p- (5 ~ pyrazolyl) = 6,7,8, 14 ~ tetrahydro ~ 6, 14 ~ endoetheno ~ thebaln implemented.

Example 30

Manufacture of 7 ^tt ° (5 ° Isoxazoiyl% ~ 7i8 "dlhydro ? 6 ° hydro3iy ° 6 * 1 4 » end oätheno oodld

Following the general procedure of Example 1, 7a-C 2-Pormy1-1-methoxyviny1) »7,8-dihydro-6 = hydroxy» 6, 14 * endoethenocodid with hydroxylamine hydrochloride in vinegar = Acid to 7a- (5 "isoxazolyl) = 7.8 <= dlhydro« 6 «hydrocycyl-6,14-endoethenooodid implemented.

example

Manufacture of

hydr Q ° »6 _r 14 - ° endoäth enonorth & bain

Following the general procedure of Example 1, N-cyano => 7ot = (2 = formyl-1 = metho3 £ yvinyl) «6,7,8,14-tetrahydro-6,14« endoethenonorthebain with hydrostylamine hydrochloride in acetic acid to N-cyano ° 7a-C5-isoxazolyl) -6,7,8, 14 = tetra = hydro-6, l4 ° endoäthenonorthebaln implemented.

909833 / U34

BATH ORIGINAL Example 32 Manufacture of N-Cfrelopropylme thy 1-70 ^ 1- (m-oftlorphenyl) ~

pavin

Following the general procedure of Example 17, tK ^ oiopropyliethyl-7a ~ (2 «= formyl -1-methoxyvinyl) -6,7 # 8,14-tetrahydro-6,14-endoHthenonororlpavin with m-chlorophenylhydrazine hydrochloride in acetic acid to give N -Cyolopropylmethyl-7o-2j- (ra-chlorophenyl) -5 "pyrazolylJ7" 6 # 7 »8,14-tetrahydro-6,14-endoethenonororipavine reacted. The Hydroohlorld crystallizes from ethanol and has a P. from 2β1 to 282 ^C C (Zere.). Xemagnetic resonancef (CDCU / d ^ ^ 7 »48 and 6.08 (PyrazolC, iH and C ^ iH, doublet« 4t-1 # 7.cps.) ·

example

Preparation of K-CyGlopropylmethyl-7a- / T- (2-pyrldyl ^^ - pyrazolyl) 7,6,7,8,14 -tetrahydro ~ 6 ^ 14-endoathenonororlpavln

According to the general Arbeltsweise of Example 17 ~ N-Cyelopropyiraethyl is 7tt- (2 = -i · ormyl-l-methoxyvin3rl) -6,7,8,14-tetrahydro- € _f L4 endoKthenonororlpavin with 2-hydrazinopyridine in acetic acid to N -Cyolopropylnethyl-7a- / T- (2-pyridyl) -5- = pyrazolylj7 "6 * 7> 8j ^ -tetrahydro-O, 14-endoXthenonororipavln converted. The compound is converted from acetone / n-hexane and has an F. from Ijj6 to 1> 8 * C.

909833 / U34

8AD ÖRJßlNAL

- 56 -

Example 34 Production of

, l4 ^c »endoethenanorl« »

6.7 # 8, 14-tetrahydro-6, 14-endoethenonororipavin, 700 mg of p ^ fluorophenylftydrazinhydroohlorld and Ao ml of acetic acid are heated on the steam bath for one hour. After cooling, the mixture is diluted with water and neutralized with dilute ammonium hydroxide. The deposited product is filtered off and dried. A solution of this product in methylene chloride is passed through a short column with Maghesol ^R. After evaporation of the eluate and recrystallization of the residue from acetone / η-hexane, 1.038 g of N ° cyolopropylmethyl-7a> 2! F '* (p ~ fluorophenyl) -5opyrazolyl7 * 6 «7» 8 _# 14 »tetrahydro-6, kthenonororlpavine are obtained from F. 151 to

Example ? 5

Manufacture of p ^ y ^ py zolyl) -6.7.8.14-tetrahydro ~ 6, 14 ° endoethenonororlpavine

1 g of N-cyolopropylmethyl ^ o-iS-formyl-1-inethojtyvinyl) -6 * 7,8,1 * -tetrahydro «6,14-endoethenonororipavin, 25 al Methanol and 0.4 ml of perchloric acid are 1 1/2 hours heated under reflux. Then 1 ml of phenylhydrazine is added and the mixture is refluxed for 1 hour. Then the solution is added dropwise with stirring to an excess of aqueous sodium carbonate and that

909833 / U34

8AD ORIGINAL

deposited product is filtered off and dried. Yield 72.8 mg, IRH spectrum

ν KBr

/ "max 6.28, 8.99 and 9 * 09 u.

540 mg of the above product are heated for 1 hour on the steam bath with 5 ml of acetic acid and 5 ml of 5% sa; isic acid without further purification. This solution is added dropwise with stirring to 20% strength by volume ammonium hydroxide solution and the deposited product is filtered off and dried. A solution of this product in methylene chloride is passed through a short column with Magnesol ^R. The eluate is evaporated to a rubbery body. A solution of this gummy body in 5 ml of ethanol is mixed with 540 mg of citric acid and the mixture is heated on the steam bath until it dissolves. This solution is poured into ether with stirring and the product which has separated out is filtered off, and ethyl acetate to 140% N ° cyclopropylmethyl 7% = ¹ (! «Phenyl-5 ° pyrazolyl) ° 6, 7, 8, 14 = tetrahydro = 6, 14 = endoethenonororipavin ° cltrat recrystallized. F. fuzzy from 90 to 140 ^e C. Nuclear magnetic © resonance: (dg ° DMSO) | 8.25 and 6.17 (pyrazole = Cri-H and C ^ ₁ -H; doublets, J ^ i, ₅ »» 2.5 cps), 5 # 65 (C ₁₇ ^ H and C ₁ Q = H; slnglett), 4.87 (C ^ H), 2 * ^ 7 (Cg- = methoxyl), 2.70 («CH ₂ ° of citrate; 2 protons or 1 mole of citric acid per mole of thebaine derivative); Bands at ί> 4.47 (Cc = H) and 5.06 (Cg = methoxy ^ j indicates the presence of about 15 % of the 7 <x ~ (l-phenyl ~ 5 = * pyrazolyl) isomer.

The mother liquor of the citrate is evaporated and the The residue is dissolved in a little methanol. This solution

909833 / U3A

6AD ORIGINAL

is added drop by drop while stirring to make 20 vol. ηiumhydroxydlösung given and the separated product is filtered off and dried. With about 220 ng of this Product becomes a distribution ohrotnatogrAphi · an Gelle 545 using the solvent system heptane / Äfchylacetat / Mtthanol / Waseer (95t5ι17 {4) carried out. The eluate is monitored at 230 μl. The faction with the maximum (fraction 6) is evaporated and the residue is dissolved in acetone. Then n ~ hexane is used until it becomes cloudy and allows the solvent to evaporate at room temperature. The residue from F. 143 bis which is 100 mg is collected. This pure. Has the following values:

_X CH, OH

λ * 259 mu (621,300); nuclear magnetic «resonance / max

£ 7.72 and 6.17 (pyrazole «e ₅ t <= H« ad C ^ t-Hj doublets, «V5is2.3 cps), 7.45 (N-phenyl? Multiple), 4.75 (C and 3.42 (C ₆ -Methcwyl), 2 _f 33 (doublet, J «5.5 cps, <]

Example 36 - ".

Production of N- cyclopropylmethyl ^ 7g ° / T ° (2 _< § ^ dlchlorphe7 nyl) H3 ° pyrazo lyl7 «6j7,8 _# l4 ~ tetralffldro ~ 6 _f l4- = endoathenonor ~ orlpavin

A hot solution of 500 mg 2,5-Diehlorpheny! Hydrazine in 20 ml of 5% hydrochloric acid is added dropwise with stirring to a hot solution of 1 g of N = cyclopropylmethyl = 7a ° (2-formyl ~ 1 = m © thoacy vinyl) «= 6,7,8,14 -te trahydro = 6, 14 = endo ~ äthenonororipavin given in 10 snl of 5% hydrochloric acid. When the addition is complete, the dl® reaction is extinguished for 20 minutes stirred for a long time and extracted with methylene chloride (for

909833 / U34

BATH ORIGINAL

solution of the material adhering to the flask, a little methanol is used). The extract is filtered and dried with 20 vol.% Ammonium hydroxide solution and then water. The dried methylene chloride solution is passed through a short column of magnesol. The column is then washed with ether. After evaporation of the eluate and recrystallization of the residue from acetone / n-hexane, 700 mg of N-cyclopropylraethyl-7a- / r- (2,5-diochlorophenyl) -5-pyr & zolfff6,7 , 8, 14-tetrahydro-6, lt-endoäthenonororlpavin from F. 161 to 163 ⁰ C (with foaming). Nuclear magnetic resonance: (CDCl *) £ 7 * 57 and 6.10 (pyraxol-C- _f -B and C ^ iH. Doublet »J, i, ^ tI, 8 ops), *, 25 (Ce-H ) *>, 27 (Cg-Wethoxyl).

Example 37

Production of N «CyoloDropy3jn» thyl-7a- (l-b <nzyl "5« pyra golyl) -6.7.8 ^ l4-tetrahydro-6 . I4 «* ndo & tbenonororlpa» in

Following the general procedure of Example 17, N «Cyclopropyliaethyl-7a- (2-form3rl-1-niethoxyvinyl) -6 _t 7.8, 14 tetrahydro-6, l% -endoäthenonororipavin with benzylhydrazine hydrochloride in acetic acid to N-cyclopropylnethyl ^ a-

nororipavin implemented. The compound is converted into ethanol crystallizes and has a P. of 195 to 197 ° C.

Example 38 Production of N-Cyolopropylaethyl-7q- (l-pentaf]

5-pyrazoly1) -6.7.8. Ik -tetrahrdro-6.14-endoHthenonororlpavin

909833 / U34

8AO ORIGINAL

ta Λ * IJ co

Following the general procedure of Example 17 is

tetrahydro "6, 14 = endoethenonororipavin with pen.tafluorophenyl" hydrazine hydrochloride in acetic acid to form N ^ cyelopropyltnefshyl " 7a- (1-pentafluorophenyl ~ 5-pyrazoly1) «6.7 * 8 * 14-tetrahydro-6, 14-endoethenonororlpavine. The connection will umkrlstaliisiert from η-hexane and has a P. from 211 to 213'C on.

Example 3? Manufacture of

^ " pyraZoly l7 ° 6» 7 _{| T} 8.14 - te trahydr o-6 _Λ 14 "endoathenonororfrpay in

A hot Se solution of 500 mg of p-Ohlorphenylhydrazishydroehlo »chloride In 20 ml of 5 £ -> hydrochloric acid is added dropwise with HtIhren to a hot solution of 1 g M" Cyclopropyljaethyl "> 7a ^a> (2-f ormyl-l <-« ethoxyvinyl) ° 6 «7e8« l4-tetrahydror6 _# l4 »end © äth @ gio · nororlpavln in 10 ml of 5% hydrochloric acid. When the addition is complete, the mixture is stirred for 20 minutes and then extracted with ethylene chloride. The set tract is washed with 20 vol ^ -iger Aligmoniuinhydroigrdlösung and water and then dried. The solution is through a® short column

nit Magnesol "After Msidaispfeü & ·" Sluats are

790 rag

6 * 7 * 8,14-tetrahydro-6.14 ° endoSthenonororipavin Als

like body obtained.

264 hu.

Example 40

vo

* 8 _Λ 14-tetrahydro-6.l4 "endolth" nonororipavifiL

909833/1434

BATH ORIGINAL

Following the general procedure of Example 39, N ~ Cyeloppropylmethyl -7a ~ C 2 'formyl -1 = methoxyvinyl) -6,7' 8,14 = tetrahydro ~ 6, l4 = endoäthenonororlpavin with m «= chlorine- · phenylhydrazine reacted in dilute hydrochloric acid, whereby man N = Cyelopropy! methyl = »7α» / Γ «(m-ehlorpheny 1) 6 # 7 * 8, l4-tefcrahydro6, l ^

after separation of the 7a ° / r ° C »n ^< = CIilorphenyl) -5-pyrft2Oljl7 = · isomers and purification by partition chromatography ·

receives. UV spectrum ν CH ^ OH

λ * 264 rough; ^ max

nuclear magnetic resonance (α ^ -Μ3θ) ^ 8.4θ and 6.20 (pyrazole Cß «= H and C ^ t-Bj doublet, J ^ i, ei = 2-2.5 cps)» 5 »86 (C ₁ WH and C ₁₈ -Hi singlet), 5 »02 (C ₅ » H), 5 * 38 (Cg-methoxyl).

Example 41

Production of H ° Cyclopropylmethyl ° 7a ° / t ° <f o ° ehlorphenyl) °

9 8 * -3-4 "tetrahydro -6.14 ° endoethenonororipavln

Following the general procedure of Example 17, N = cyelopropylmethyl = »7a ° ^> (2-f omiyl ^ 1-methoxyvinyl) = 6,7,8 * 14-tetrahydro = 6,14 ~ endoethenonororipavine with o-chlorophenyl = hydrazine hydrochloride in acetic acid converted to N-cyclopropylmethyl "7a- ^ l ^5o {o" = chlorophenyl) = 5 = pyrazolyl.7 ⁱ = 6,7,8,14 "tetrahydro" = 6s I4 <= endoethenonororipavine.

Example 42

Production of H ^ Cyclppropy! Methyl ° 7q ° / r ° Cp ° ohlorph enyl) ° 5 ° pyrazolyl 7 ° 6 _J 7 _J 8 _J , l4 ° tetrahydro-6 ₁ l4 ° 'endoathenonororipavin

909833 / U34

ßAO ORIGINAL

Following the general procedure of Example 17, N-Cyolop? Opylfnet * yl "= 7a ° (g-foiiqyl
l ^ -tefcrahydro ^, l% ~ endoäthenonororipii ¥ iiii with phenylhydrazine hydrochloride in EssigsSw® an

feetrahydro-6,

Belgpiel

.from

Do the general procedure of Example 17

hydrazine hydrochloride in vinegar ^ acid eu iJ-Syelopropylraethyl

7a »^ ™ (ni-fluoi ^ henyl) ^ 5 °

l ^ -endoäthenonororipavin

Example kk
Made by

Following the general procedure ^T / on Esispiel 17 N ~ Cy c lopropy lme tfcyl "" 7 "^ C 2" formyl "= *! "Aistisojsyviny 1)" 6, 7, 8, tetrahydro "6, @ l4 ° ndoäthenGnororipavlß hydrazlnhydrochlorld salt in acetic acid to

6, l4 ° andoäfeheiionororipavin

909833/1434

6AD OfUGlNAL

Example 4ß Production of

In accordance with the general procedure of Example 17, N-cyclopropylmethyl-Ta-Ca-forrayl-6,7,8,1% tetrahydro-6,4 ° endoethenonororipavin with n-broaphenylhydrazine hydrochloride in acetic acid zu) f <Ofelopropylitetlgrl < 7 * - / £ - (m * broapnenyl) -5-pyi * »« ply ^ -6 # 7 # 8, l4-t «trahydro» 6, 14-endoKthenonororipavin implemented.

Bejgplel 46

Heratelltmjt by N ~ Cyclopropy ! methyl-Ta'A- a-tolyl) -g-oyra2olyl7 '"6i ₍ 7" 8 _< 14-tetrahydro "6.14 ° nororipavin

Following the general procedure of Example 4, N-cyclopropylmethjrl-7a- (2-förngrl-1-iaetluMqnriayi) "69796" 14-tetrahjdro-6,14-endotthenonororipavin ait α, α, α-trifluorom-tolylbydrazine-hardigroohlorid Cyolopropylaethyl -7α- ^ Τ- (α, α, α-trifluor-et olyl) -S-pyraxoly ^ "6> 7 * 8, l4-tetrahydro-6,14« endoäthenonororipavln unset ·

Example »7

Production line of lt- ^ yoloproiylsjetiiyl-7 «- / f-fa-toly ^) -« i .7.8 _a l4-

After the general work we know from example 4

909833/1434

.- ■. ■ ./- ■., 8AD ORIGINAL

tetrahydro <*> 6 »34« endoäthenonor0ripavin with ra hydrochloric in acetic acid e «K ^ Qyelopropylraefeharl-Te- (m-tolyl) "5 = pyrazoly ^ 7" 6.7 * 8 set.

Example 48

Preparation of N _i "cyclopropylmethyl ° 7a '(l-methyl» g;

Following the general procedure of Example 4

tetraiiydro ~ 6, 14 «endoKthenon0i <oripav.tn with methylhydtrazisi« hydrochloric in acetic acid to form N ^ oyolopropylmethyl 7α (1 iaethyl [5-pyrasolyl] ~ β, 7 * 8, 14 nororipavin implemented.

7g-pyr ^^^

the general Arbeitsweise® ¥ on example 17 becomes

6 »l4-endo8th @ iionororipavin with

converted into SssigsSur® jsu N "allyl-7e- (l-pheayl" 5-pyra2olyl) "6 _# 7 _# S, 1% tetrahydro" 6,14-endoethenonororipavine.

909833/1434

i BAD ORK3JNAL

Example 50

Production of N »Allyl? Tg? /? - (m? ClllQgphen, ylX-5 ° pyragol yl7 ^q 6,7,8, l4-> tetrahydro ° -6, 14 ° endollthenonororipavln

Following the general procedure of Example 17, N-allyl-7a- (2'formyl ~ l ~ methoxyvinyl) -6,7,8,14 «tetrahydro-6,14-endoethenonororlpavln is converted with m-chlorophenylhydrazine hydrochloride in acetic acid to form N- Allyl ^ a ^ / k-ira ^ ehlorphenyl) ^ = pyrazolyl7 ~ 6,7,8,14 »tetrahydro-6,14-endoäthenonororipavln implemented.

Example 51

Manufacture of N ^ / ^^ methyl «g-butene- = '! ^ YI) ₁ *» (β pyrazoly l) ° 6 _ff 7 ff8 ₁ , l4-tet rahydro ° 6 _t l4 ° gndoäthe ^^

Following the general procedure of Example 17 is N »(jJ Methyl-2» l) uten «» l => yl) »7a = (2 = 'forniyl-l = metho3qfvinyl) =' 6,7 * 8,! ^ "Tetrahydro-ejl ^ endoöthenonororipavin rait Phenyl" hydrazine hydrochloride in acetic acid to N ° (3-methyl = 2 <= butene *

endoethenonororipavin. implemented.

example

Production of N ° C3-4gethyl ° 2 - = 'butene' »l ° yl) ° '7a ° / r ° Cn ° Hshlor · phen yl) ° 5 ° pyrazoly3 ^ ° 6 ₁ Ί _Λ Z ₃ l4« tetrahydro ° 6 » I4« endoätheno « nororipavln

Following the general procedure of Example 17 is N- (j5 = methyl ~ 2 ° buten-l-yl) ° 7a «(2-formyl

909833 / 143A

BAD ORlGIMAL

6.7 * 3 * l4-tetrelqrdro-6 , l% - @ n & oSfcIi «ttoii © 2? Opipavi« «it. ra-ChlorophenylhydrazinijyöSOelilorla in Bsslgeiw «« t ' N- (3-methyl-S-buten-1-yl) <

pavln implemented,

Example l®! ^

pavln

Following the general operation of Example

l% -tetrahydro-6 ^ l4 «= © n <äoEtlieK € mororipaviÄ ailfe hydrazine hydroehloriä in acetic acid to M

6, l4 «endoäthenonoi ⁱ oripairiii implemented ®

example Manufacture of

nyl) «-5-

nororipavin Following the general procedure of Example 4,

rait phenylhydrazine hydrocarbon in Itssigs & we to N-cyclobutyl-

909833/1434

8AD ORiGINAL

hydro-6,14 ~ endoäthenonororipavin implemented.

example

Preparation of 7a- (2 ~ Po3TOyl-l ^ ethoxyvinyl) "6 _f 7.8 _> 147 tetrahydro-6, lfr-endoSthenothebain

A solution of 20 g of phosgene in 200 ml of methylene chloride is quickly added dropwise, with stirring, to a mixture of 200 ml of dimethylformamide (dried over molecular sieves) and 600 ml of methylene chloride. After the addition is complete, the mixture is stirred for a further 15 minutes. For a solution of 19.4 g of 7o "(l, l-dinsethoxyethyl) -6.7 * 8, 14-tetrahydrQ" 6,14-endo-thenothebaine in 200 ml of methylene chloride and 10 al of pyridine is added slowly and the Mix 45 minutes. 1200 ml of 5% aqueous sodium acetate are then added and the mixture is stirred vigorously for 30 minutes. If necessary, the mixture is adjusted to pH 8 by adding aqueous sodium carbonate solution and the layers are separated. The aqueous layer is washed with methylene chloride and then made strongly alkaline with 10 ml of Hatriuahydroxydissung. The mixture is extracted with ether and the extract washed with water and dried. After evaporation of the solvent and faklatalisation of the residue from aoeton / n «Rexan, 15.37 g of 7a- (2-formyl-1-methoxy viny 1) -6.7 # 8, 14-th trahydro-6,14-endoKthenothebain are obtained from P. 152 to 15> * C. A further 1.42 l of product from P. 150 to 152 ° C are obtained from the mother liquor, so that an oesant yield of 87 % is achieved.

909833/1434

BATH ORIGINAL. Example 56

Manufacture of W ^ Cfre lopyppylmefchyl ^ methoxy vinyl) ° 6 _M 7 _f 8 _F l% te trahydro ° 6.1 fr ~ endoetharK> nor th »° bainhyd roohlorid

A solution of 1 g of phosgene in 10 ml of methylene chloride is quickly added dropwise with stirring to a mixture of 10 ml of dimethylformamide (dried over molecular sieves) and 50 ml of methylene chloride. When the addition is complete, the mixture is stirred for a further 15 minutes. Then a solution of 1 g of N <^ elopropylmethyl-7a ° (l * l ~ dimethoxyethyl) '= 6,7,8,14 <M; etrahydro = 6,14 «= endoethenonorthebain in 10 ml of methylene chloride is added in a slow stream 0.5 ml of pyrldine are added and the mixture is stirred for 45 minutes at room temperature. Then 60 ml of 5% aqueous sodium hydroxide solution are added to the mixture and the mixture is stirred vigorously for 30 minutes. The layers are separated and the organic phase is washed with water and dried. The oil obtained after evaporation of the solvent is dissolved in 5 # hydrochloric acid and the solution is washed with ether and extracted with methylene chloride, the extract is dried and evaporated. Acetone is added to initiate crystallization. After filtering off the product with the addition of ether, 825 mg of N-Qyolo "propylmethyl-7a ~ (2" forrayl ° l -raethoxyvinyl) "6,7,8,14 -tetrahydro-e ^ -endoethenonorthebain hydrochloride from F. 213 to 215 ^# C.

909833/1434

^{0 i:} " 8AD ORiGlNAL

ftelspiel

Production of

hydro «» 6 _a l4 »endoethenoorlpavin

Following the general procedure of Example 56, 7 «- (1,1 «DimethoxySthyl) = 6,7,8,14 -tetrahydro» 6,14 ~ endoetheno ~ oripavin reacted with phosgene ^ Dieinthylformamid and an » finally hydrolyzed, whereby 7 <x- (2 «'Formyl ~ l-ffietho: jty = vinyl) «6,7,8,14-tetrahydro-6,14 ° endoethenooripavin.

example

Production of H °° Gyclopropylmethyl «7 a ° (g ° forinyl« »l" i yethO'Xy7 vinyl) "6 _J , 7 _J 8, 14 ° tetrahydro" 6, 14-endoetheno nor or Ipavin

A solution of 8.5 g of phosgene in 255 ml of methylene chloride is drop by drop with slow stirring to a mixture of 85 ml dimethylformamide (dried over molecular sieves) and given 255 ml of methylene chloride. 15 minutes after finishing » The addition is a solution of 8.5 S N ° Cyelopropylmethyl » 7a ° (1,1 ° dimethoxyethyl) = 6,7,8, 14 ° tetrahydro-6, 14 ° endoethenonororipavln in 85 ml of methylene chloride and 4.5 ml of pyridine added in slow flow and the mixture is at room ' stirred temperature for 45 minutes. Then the mixture 510 ml of 5% aqueous sodium hydroxide are added and Vigorously stirred for 30 minutes. The layers are separated and the methylene chloride extract is mixed with water. wash and dry. After evaporation of the solvent, a rubber-like body is obtained, which when added Water solidifies. This product is collected and dried as a methylene chloride solution. After evaporation of the

909833 / U34

SAD ORlGlNAi.

Solvent are 8 g (quantitative yield) of N-Cyclo propylmethyl = 7a- (2 ~ formyl ^ l ^ ethoxyvinyl) - = 6.7 "8, ^" tetrahydro "^, 14" "ndoäthenonororipavin as a vitreous body obtain.

February 59

Manufacture of y ^^^^^^) ^^^! ^^^^, te trahy dro «-6,14-endoethene onorthebain

Following the general procedure of Example 56 becomes

northebain reacted with phosgene dimethylformamide. Connect < send is hydrolyzed. 7a ~ (2 = Forrayl ~ l <= methoxy ° vinyl) »6,7,8, ^» teträbydro ^ ö * l4 ~ endoäthenonorthebain.

Example 60

Division of 7 "° C Rr ^ egfyjk? J- ° Pf ffiff ^ ff" ^ ° butenyl ·) -6 _f 7 _f 8.14 ° »tetrahydrο ° 6 ^ 14 ° end oäthen othebaln

According to the general procedure of Example 55, the addition of 7a "(1,1 -dirnethoxybutyl) 6,7,8,14-tetrahydro" 6,14-endoethenothebaine with phosgene ^ bimethylformamide and subsequent hydrolysis 7a = (2 «ForB ^ l = l ° methoxy »l ° butenyl) =» 6,7,8,14 ° tetrahydro-6,14 => endoethenoth8baln produced.

Example 6 l production of

tetrahydro ° 6 _f l4- ° a ndoSthanot hebain

909833/1434

BATH ORIGINAL

Following the general procedure of Example 55, by reacting 7a ~ (l, l ~ dimethoxyethyl) -6 _# 7 # 8 # 14- »t8trahydro» 6,14-endoethanol with phosgene dimethylformamide and subsequent hydrolysis 7a- (2-Ponn3rl -1-methoxyvinylnyl} -6,7,8,14 = tetrahydro-6,14- «ndoethariothebaine.

example 62

Production of 7 ^ - (2-Pormyl ° l ° metho3cyvinyl>'- 6 _J 7.e _f l4-tetrahydro-6, l4-endoäthenothebaine

According to the general procedure of Example 55, by reacting 7β ~ (l, l-diraethoxyethyl) -6,7,8,14-tetrahydro-6,14 "endoethenothebaine with phosgene-dimethylformamide and subsequent hydrolysis 7S- {2-Porßyl" methoxyvinyl) -6,7,8,14 «te trahydro® 6,14-endoKthenothebaine obtain.

Example 63

Production of 7a- (2-Porniyl-1-Methoxyvlnyl) "7.e-dlhydro" 6-hydroxy-6.l4-endo & thenooodld

According to the general procedure of Example 55, the reaction of 7a- (l # l-dimethoxyethyl) -7 # 8-dihydro-6-hydroxy-6,14-endoethenoco <Jid with phosgene-dloiethylformamide and then hydrolysis 7a- ( 2-poreyl-l- "ethoxyvinyl)" 7 _# 8 "dihydro-6 ° hydroxy-6 _J 14" endoKthenocodld produced.

909833 / U34

BAD ORJGlNAV

Example 64 Production of

S. l * "tetrahydro ° 6, lfr-endoKthenenorthebaln

According to the general procedure of Example 55, by reacting N-cyano-7a »(l, l-dimethoxyethyl) -6.7, 8, l * -tetrahydro ° 6 _a l ^ -endoäthenonorthcbain with phosgendimethylformamide and subsequent hydrolysis of N-cyano -

endo & thenonorthebaln received.

Example 65 Production of N-Allyl ^ c-fg ^ fonmrl-l-methoaQrvinyl) »

According to the general procedure of Example 56, the reaction of N * allyl-7a- (l, ldlmethoxy & thyl) -6.7 _e 8, l * -tetrahydro <-6, 14 "endo & thenonororipavin with phosgendlmethylformamide and subsequent hydrolysis of N-allyl ~ 7cc - (2-forayl-1-hoethoxyvinyl) «6,7,8,14-th trahydro-β, 14-enäoäthenonororlpavin produced.

example 66 Production of 7g «(2" Pormyl-1HBethoxyvinyl) -N * (3Hn »thyl '

7> 8.l4 '· tetrahydro «^. I4» endoäthenonororl-

According to the general procedure of Example 56, the reaction of 7o- (l _i l-DimethoxyHthyl) -N-OHneth7l-

909833/1434

BATH ORIGINAL

6.7 * 8 " 14 = tetrahydro ° 6, 14 ~ endoethenonori ~ pavine with phosgene = dimethylformamide and subsequent hydrolysis 7α- (2 ° Forrayl ~ l« = methoxyvinyl) «Ν- (5-raethyl-2-butene l ~ yl) = 6,7,8,14 => tetrahydro ~ 6, 14 ~ endoethenonororipavine obtained.

example 6y Manufacture of N °> cyclobutylmethyl "7tt"'(g ° fomiyl- "l °

methoxy vln yl) «° 6 _f 7 _<f 8 _f l4 ° tetrah ydro '= - 6 _f l4» endoethenonor-

oripavln

Following the general procedure of Example 56 is made by reaction of N-cyclobutylmethyl ^ a-fljl-diraethoxyethyl) -6.7 * 8 «14« tetrahydro = 6.14 = endoethenonororipavin with phosgene diraethylforinainide and subsequent hydrolysis

tetrahydro ^, 14-endoäthenonor or ipavin produced pebble 68

Production of ^ "Cycloprop ylmethyl ^ tt ^ ri-phenyl ° 5 °; zolyl) ° 6 _f 7 , 8 , 14 ° tetrahydro ° 6, 14 ° endoäthenonororipavin

The compound N ^ yclopropylraethyl ~ 7a- (l ~ phenyl = 5-pyrazolyl) -6,7,8,14-tetrahydro-6,14 ° endoethenonororipavln becomes standard pharmaceutical products according to the following recipe Tablets processed:

909833 / U34

BATH

component

per tablet

mg>

for 10,000 tablets, g

N-Cyolopropylmethyl =? «- (lhl ^ ll)

py ^ pyy) , 7 * 8,14 ~ tetrahydro ~ 6, endoäthenonororipaviii

2.5

25th

Lactose

Corn starch (for mixing) Corn starch (for paste) Magnesium stearate

225 .2250 50 500 25th 250 5 50

307.5

3075

The active ingredient, the lactose and the corn starch to mix are mixed together. The cornstarch for fasting is in water in a ratio of 100 g of corn starch suspended per 800 ml of water and heated with stirring, until a paste forms. The fast obtained is then Used to granulate the powder mixture, if necessary, additional mass is used. The wet grains are passed through a 2.38 mm (8 mesh) mesh screen and dried at 49 ° C (120 ° F). The dry grains are borrowed through a sieve with a = th mesh size of 1.19 mat (1β mesh) and with made lubricious to the magnesium stearate. Then that will Granules are compressed in a * tableting machine, see below tablets (Tablet weight 355 mg). Each tablet contains 50 mg of active ingredient.

909833/1434

8AD ORIGINAL

pelspiel g

Manufacture of N ° Cyolopropyl-ethyl-7tt- /! F "fa-chlw ^ phenyl ) - «» - pyrazolyl) 7 · »6 _f 7 » 8th , lh ~ tetrahydro-6. 14 ~ endoathenonororlpavln

The substance N ° cyclopropylrethyl-7a- / f- (ra-ohlorphenyl) -5-P3n ^t azoljrlJ7 "6 # 7" 8, 14-tetrahydro6,14-endoethenonororipavin can be administered in the form of capsules with a hard shell The following preparation has proven to be advantageous for the production of such capsules:

Ingredient per capsule. for 1000

■ g capsules «g

N-cyclopropylraethyl ^ a- 2.5 2 * 5

^ IXhlhlS

^ XpySpy «olylj2-6 # 7 # 8 _# 14-tetrahydro-6 _# 14-endottthenonororipavln

Lactose 90 90

Magnesium stearate 1.5 1

9 * 9 *

The active ingredient, the lactose and the Hagneaiuastearat are old to each other. The solution becomes Capsules, hard-shell capsules suitable for the bit a filling weight of 9% mg per capsule was used.

909833 / U34

BATH ORIGlNAt

Example 70 Manufacture of

pyrazolyl) -6,7.8.14-tetra h y dro «6 _f 14 -enflo & thenonororipavin

The active ingredient N = Cyülopropyliuethyl-7a »{l- ^ enyl-5 '» pyrß «'

can be used as an injectable «solution to» according to the following recipe to be prepared:

Ingredient l

N-Cyolopropyliaethyl-Ta-Cl-propyl-5-pyrazolyl) ^, 7,8, 14-tetrahydro ~ 6, l4-endo & thenonorlpavin 0.1g

Polyethylene Glyool 4000 U.S.P. 4.0 g Sodium chloride U.S. F. 0.90 g Benzyl alcohol, reagent grade 0.90 g Water for injections up to 100.0 ml

The carrier is made by mixing together all of the above-mentioned components except for N-cyclopropylmetyl-Ta-Cl-pfceuyl-5-pyx * solyl) -6,7,8,14-tetrahardro-6,14 «endoethenonoripavin prepared. The carrier and active ingredient are sterilized by suitable cafeteria. A solution of the active ingredients in the carrier is made by adding the active ingredient first dissolves with part of the carrier and then the remainder of the carrier is added with stirring.

A 1 nl dose of this solution therefore contains 1 mg of active ingredient.

909833/1434

! SAD ORIGINAL

■ T If '!!!! «·' ¹

- 57 -

Example 71

Production of N ° C ycloprop y! Methyl '

phenyl ° »5 ° pyrazolyl ) Y ° 6? f _f 8, 14-tetrahydro-6j l4 "endoKtlitno" *

nororlpavin

The active ingredient yppyy ^ 5-pyrazolylJi7 ^e 6 # 7 * 8, 14-tetrahy <3ro-6, 14 ° endoUthenonororipavin can be prepared as an injectable solution according to the following recipe.

Beatand part

yppy7 (

chlorphenyl) -5-PyTaZoIyIX ^ '=' 6,7,8 "^ -tetrahydro-ö, I4" endo " ethenonororipavin 0.1 g

Polyethylene Glycol 4000 U.S.P. 4.0 g Sodium Chloride U.3.P. 0.90 g Benzyl alcohol, reagent grade 0.90 g Water for injections up to 100.0 ml

The carrier is prepared by mixing all of the above-mentioned ingredients except for N ~ cyolopropy / methyl "7α- ^" (aiHShlorphenyl) -5 ~ pyrazolyl27 ^e 6 # 7 # 8,14 = »tetrahydro = 6, 14 ° endoethenonororipavin . The carrier and the active ingredient are sterilized by suitable means. A solution of the active ingredient in the carrier is prepared by first dissolving the active ingredient with part of the carrier and then adding the remainder of the carrier with stirring.

A 1 ml ~ Do8is of this solution contains 1 mg of active ingredient.

909833 / U34

BAD GR (GlNM.

Claims (3)

50 β claims. 1. Process for the preparation of compounds of the formula R-, wherein R _{1 is} hydrogen, a lower alkyl radical or lower alkanoyl radical; R _{2 is} hydrogen, a cyano group, a propargyl radical, lower alkyl radical, phenyl lower alkyl radical, lower alkenyl radical or lower cycloalkyl methyl radical; R, hydrogen or a methyl radical; Y is a fifcheno = or kthano group and Q is a radical of the formula Z. C = Ri. or means in which R ^ is hydrogen or an alkyl radical with 1 to 7 carbon atoms and Z is the group. 909833 / U34 BAD ORIGJNAl. ₅ IT-, -OH * or -HC (HH ₂ ) -N-, where R _{5 is} hydrogen, a lower alkylreat, phenylrea, halophenyl, lower alkylphenyl, lower alkoxyphenyl, pyridylrea, quinolyl, benzthiazolyl, diaetbylpyriaidyl or Dl » Ethjrls-trlasinylrest is »characterized by the fact that one connects the Forael wherein R ^, R ₂ , R «,. R ^ and Y are as defined above and Rg is a lower alkyl radical, to form the heterocyclic radical bit of a hydrazine of the formula HN (Rc) -MH ₂ , in which R ₅ is defined as above, or hydroxylamine, guanidine or their salts in one Proton-containing solvent at a temperature of 50 to about 125 ° C and the product is obtained from the reaction solution. 909833 / U34 2. The method according to claim 1, characterized in that compounds of the formula where R ^ is hydrogen, a lower alkylate or lower Alkanoylreetj It ₂ Waaaeratoff » a cyano group, a propargylrea, lower alkylreat, phenyl» lower alkyl, lower alkenylrea or lower Cyoloalkylmethylrestj R, water or a methyl reati R ^ Vaaaeratoff or an alkylreat with 1 bia 7 Carbon atoms R hydrogen, a lower alkyl radical, phenyl radical, halophenyl radical, lower alkylphenyl radical, lower alkoxyphenyl radical, trifluoromethylphenyl radical; Fyridyl residue, Cbinol.ylreat. Bönzthl * - KOlylreate JDlmethylpfyriniidyircst or Dimethyl · *: »triaxinylreat and t means an Xtheno ~ or Kthano group | or their non-toxic acid addition or _} if R _{1 means} a hydrogen atom, produces their alkali phenolates. 909833/1434 BATH ORIGINAL 3. Compounds «characterized by the formula wherein R _{1 is} hydrogen, a lower alkyl radical or lower alkanoyl radical; R _{2 is} hydrogen, a cyano group, a Fropargyl radical, lower alkyl radical, Phenylnlederalkylrest, lower alkenyl radical or lower Cycloalkylmethylrestj R * hydrogen or a methyl radical; Y is a ktheno or ethano group and Q is a radical of the formula Rj, or * r \ "/ denotes in which Rj is hydrogen or an alkyl radical 2nlt 1 to »7 carbon atoms and Z the group - N », -0-K = or -N-C (NHg) -M-, where R- is water« substance, a lower alkyl radical, phenyl radical, halogen phenyl radical, lower alkylphenyl radical, lower alkoxyphenyl rest, pyrldyl radical, quinolyl radical, benzthlazolyl radical, Dimethylpyrltnidylrest or Dimethyls-trlazinylrest is. 909833 / U3Ä BATH ORIGINAL . Compounds according to claim 3, characterized by the formula wherein R _{1 is} hydrogen »a lower alkyl radical or lower alkanoyl radical # H ₂ hydrogen» a cyano group, a propargyl radical, lower alkyl radical, phenyl lower alkyl radical, lower alkenyl radical or lower cyoloalkylmethyl radical; R- is hydrogen or a methyl radical; R ^ is hydrogen or an alkyl radical having 1 to 7 carbon atoms; Typically hydrogen, a lower alkylreot, phenyl radical, halophenyl radical, lower alkylphenyl radical, lower alkoxyphenyl radical, trifluorotethylphenyl radical, fyrldyl radical, quinolyl radical, benzthiazolyl radical, dimethylpyrimldylreet or dimethyl radical, trlazinyl radical and Y denotes a ktheno or Xthano group Acid addition salts and, when R _{1 is} hydrogen, their alkali phenolates. 909833/1434 SAD ORIGINAL