IL31080A - 7-pyrazolyl,isoxazolyl or pyrimidinyl-7,8-dihydro-6-(hydroxy or methoxy)-6,14-endo(etheno or ethano)codides and morphides and process for their preparation - Google Patents

Description

-PYRAZOLYL, ISOXAZOLYL OR PYRIMIDINYL-7, 8- IH YDRO - 6 - ( HYDROXY OR METHOXY)-6, 14-ENDO(ETHENO OR ETHANO) CODIDES AND MORPHIDES AND PROCESS FOR THEIR PREPARATION i ans) Π3κ-ΐ4,6-( «ορηηο ικ «ορτ η'η)-6-ι Π'ΠΊ This invention relates to novel substituted 7-heterocyclic-7,8-dihydro-6-(hydroxy or methoxy ) -6, 14-endo(etheno or ethano) codides and morphides and to methods of preparing these compounds . The novel compounds of the present invention may be represented , by the following general formula: (I) wherein Ri is hydrogen, lower alkyl or lower alkanoyl; R2 is hydrogen, cyano, propargyl, lower alkyl, phenyl lower alkyl, lower alkenyl or lower cycloalkylmethyl; R3 is hydrogen or methyl; Y is etheno or ethano; and wherein R4 is hydrogen or alkyl of from 1 to 7 carbon atoms; and Z is -N(R5)-N=, -0-N= or -N=C(NH2)-N= wherein R5 is hydrogen, lower alkyl, phenyl, halophenyl, lower alkylphenyl, lower alkoxyphenyl, trifluoromethylphenyl, pyridyl, quinolyl, benzothiazolyl, dimethylpyrimidyl or dimethyl-s-triazinyl . Suitable lower alkyl, lower alkoxy and lower alkanoyl groups contemplated by the present invention are those having from 1 to 4 carbon atoms such as methyl, ethyl, isopropyl, n-butyl, methoxy, ethoxy, n-propoxy, n-butoxy, formyl, acetyl, propionyl, isobutyryl, etc. Typical alkyl groups of from 1 to 7 carbon atoms are, for example, methyl, ethyl, n-propyl, n-butyl, isoamyl, sec . - hexyl, n-heptyl, etc. Suitable lower alkenyl groups are those having up to about 6 carbon atoms such as, for example, allyl, meth-allyl, dimethallyl, and the like. Suitable lower cycloalkylmethyl groups are those having from k to 7 carbon atoms such as cyclopropylmethyl, cyclobutylmethyl, cyclo-pentylmethyl, etc. Phenyl lower alkyl is exemplified by benzyl, a-phenylethyl, β-phenylethyl, and the like. Suitable halophenyl groups are, for example, p_-fluoro- phenyl, p_-chlorophenyl, m-chlorophenyl, m-bromophenyl, o-fluorophenyl, 2,5-dichlorophenyl, 2, k , 6-trichloro-phenyl, 3* -dichlorophenyl, 2, 6-dibromophenyl, penta-fluorophenyl, etc. Suitable lower alkylpheny1 groups are, for example, p_-tolyl, m-tolyl, o-tolyl, p_-ethyl-phenyl, p-isopropylpheny1, m-isobutylpheny1, etc. Suitable lower alkoxyphenyl groups are, for example, m-methoxyphenyl, £-methoxyphenyl, m-ethoxyphenyl, p-iso-propoxyphenyl, etc. Pyridyl, quinolyl and dimethyl-pyrimidyl are exemplified by 2-pyridyl, 5-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolylj k , 6-dimethyl-2-pyrimidyl and 5, 6-dimethyl-2-pyrimidyl . It should be noted that when Z is -N=C(NH2)-N= then structures (A) and (B) represent two resonance forms of the pyrimidine ring; and when Z is -NH-N= then structures (A) and (B) represent tautomers of the pyrazole ring.

The novel compounds of the present invention are generally obtainable as crystalline materials having characteristic melting points and absorption spectra.

They are appreciably soluble in many organic solvents such as ethanol, chloroform, benzene, ethyl acetate, and the like. They are, however, generally insoluble in water .

The organic bases of this invention form acid-addition salts with a variety of organic and inorganic salt-forming agents. Thus acid-addition salts, formed by admixture of the organic free base with an equivalent amount of an acid, suitably in a neutral solvent, are formed with such acids as sulfuric, phosphoric, hydrochloric, hydrobromic, citric, lactic, tartaric, acetic, gluconic, ascorbic, and the like.

Also, included within the purview of the present invention are the alkali metal salts (e.g., sodium and potassium) of the organic free bases when Ri in the above general formula is hydrogen. For purposes of this invention, the organic free bases are equivalent to their acid-addition salts and their alkali metal salts .

The novel substituted 7-heterocyclic-7,8-di-hydro-6- (hydroxy or methoxy ) -6, l4-endo( etheno or ethano) codides and morphides (IA) and (IB) of the present invention may be readily prepared by treating an appropriately substituted 7-(2-formyl-l-alkoxyvinyl)derivative (II) with a heterocycle-forming reagent in accordance with the following reaction scheme: wherein Rx, R2, R3, R4, Z and Y are as previously defined and Re is lower alkyl . By this procedure, a suitably substituted 7-[di( lower alkoxy )methyl]derivative (IV), prepared as described in Belgian Patent No. 71^ , 3^9* is treated with a formylating agent followed by hydrolysis and the intermediates (II) are isolated directly. Alternatively, a suitably substituted 7-( 1-alkoxy-l-alken-l-yl) derivative (III), prepared as described in Dutch Patent Application No. 68.05648, published October 28, 1968 may be converted to the intermediates (II) by formylation and hydrolysis. By this route, the 7-(l-alkoxy-l-alken-l-yl) derivatives (III) may be isolated and purified or may be prepared "in situ" and formylated without isolation or purification depending upon the circumstances.

The formylating reagent is prepared by treating a substituted formamide such as N, -dimethyl ormamide, Ν,Ν-diethylformamide, N-formylpiperidlne, N-formylmor-pholine, N-methylformanilide, and the like, with phosgene, phosphoryl chloride or thionyl chloride in an inert solvent such as methylene chloride, ethylene chloride or chloroform. Alternatively, an excess of the substituted formamide may be used as the solvent. The formylation reaction (IV—» II or III-^II) is also most conveniently carried out in an inert solvent such as methylene chloride, ethylene chloride, chloroform, or an excess of the substituted formamide employed to prepare the formylating reagent. The temperature range for the formylation reaction is from about 0°C. to about 35 °C. although room temperature is preferred. The hydrolysis step may be carried out with dilute acid or ' dilute alkali but preferably with aqueous sodium acetate When the formylation reaction is substantially complete (usually from several minutes to several hours or more), the reaction mixture is stirred with aqueous sodium acetate or aqueous sodium hydroxide for from several minutes to several hours at room temperature and the product is isolated. The above described formyl lation reaction may be considered to be effected via a formylating reagent such as that shown by compound (V), the formylating reagent formed from N,N-dimethylfor-mamide and phosgene. This formylating reagent then reacts with the ketal (IV) or enol- (V) (VI) -ether (III) to form an i inium intermediate (VI) (partial structure only shown) which is converted by hydrolysis to the intermediates (II).

The conversion of the 7-(2-formyl-l-alkoxy-vinyl) derivatives (II) to the corresponding 7-hetero-cyclic-7,8-dihydro-6- (hydroxy or methox ) -6, 1 -endo-(etheno or ethano)codides and morphides (IA) and (IB) of the present invention may be readily accomplished by treating an appropriately substituted 7- (2-formyl-1-alkoxyvinyl) derivative (II) with a hete.rocycle-form-ing reagent such as hydrazine, a substituted hydrazine of the formula R5NH H2, hydroxylamine or guanidine .

By this scheme, selection of the heterocycle-forming reagent and the appropriate condensation conditions then determines the isomeric form of the product as (IA) or (IB). For example, when the heterocycle-forming reagent is hydrazine, the products (IA) and (IB), where Z is -NH-N=, represent tautomers of the pyrazole ring. As such, these tautomers are not ordinarily separable, and the tautomeric structure of an individual product in crystal form or in solution is determined by the individual properties of the specific compound. Physical methods such as infrared, nuclear magnetic resonance and ultraviolet spectra may be useful in determining tautomeric formulae as is X-ray cyrstallographic analysis, also.

When the heterocycle-forming reagent is a substituted hydrazine (R5NHNH2) or hydroxylamine, the products (IA) and (IB), where Z is -N(R5)-N= or -0-N=, represent pyrazole or^ccazole ring isomers capable of individual existence and separation from each other with distinct and different properties. The isomer formed in a given condensation reaction is governed by the specific condensation conditions (solvent, temperature, etc.), and the individual condensing reagent (substituted hydrazine or hydrox lamine) , The products of these condensation reactions may be one isomer or the other (IA or IB) in a substantially pure state or a mixture of the two isomers. Methods of separation and purification well known to those skilled in the art such as extraction, fractional crystallization, chromatographic separation and purification and the like may then be used to isolate the individual isomers (IA and IB).

Physical methods particularly including nuclear magnetic resonance and ultraviolet spectra are useful in establishing the isomeric structure of individual condensation products (IA or IB).

When the heterocycle-forming reagent is guanidine then structures (IA) and (IB), where Z is -N=C( H2)-N=, represent two resonance forms of the pyrimidine ring.

These condensation reactions are conveniently carried out in solvents such as acetic acid, dilute hydrochloric acid, ethanol, propanol and the like. The temperature range employed is from about 50°C. to about 125 °C. with the preferred range being from 8o°C. to 125 °C. The reaction is conveniently carried out by heating on the steam bath or at the refluxing temperature of the solvent, and is substantially complete within about one hour to several hours or more. The novel products of the present invention are isolated therefrom and purified by standard procedures.

A more specific embodiment of the novel process (II—^IA or IB) of the present invention may be illustrated by the following reaction scheme: wherein Ri, R2, 5 and Y are as previously defined.

By this procedure, an appropriately substituted 7-(2-formyl-l-methoxyvinyl) derivative (IIA) is condensed with a hydrazine derivative RSNHNH2. The condensation products are the isomers (IC) or (ID) which may be isolated in substantially pure form or obtained as mixtures and separated by well known methods. The nuclear magnetic resonance and ultraviolet spectra of these com- pounds provide definitive structural assignments .for these pyrazole isomers. For example, a specific pair of isomers derived from condensation with phenylhydrazine is illustrated by (VII) and (.VIII) (partial structures only shown) related to (IC) and (ID), respectively: The nuclear magnetic resonance and ultraviolet spectra of (VII) and (VIII) (Ri=H, R2=cyclopropylmethyl, Y= etheno) are characteristic for the pyrazole isomers.

The pyrazole olefinic protons in the nuclear magnetic resonance spectrum of (VII) (C3l-H and C4,-H, doublets at jfT. 0 and <£6.i;3, respectively, in de-DMS0) have a coupling constant of l.b cps, whereas the coupling constant of the analogous protons in isomer (VIII) (C5 -H and C4,-H, doublets at ef .25 and efS.lJ, respectively, in de-DMS0) is numerically larger (i.e. 2.5 cps), as expected. In addition, the N-phenyl protons of the l-phenyl-5-pyrazolyl isomer (VII) appear as a sharp singlet at £7. ^, while those of the 1-phenyl--3-pyrazolyl compound (VIII) appear as a broad multi-plet at «ί7.2-8.0 indicating non-equivalence of the £,m- and p ' ,m' -protons in this isomer. This suggests an unhindered, co-planar and conjugated conformation between the phenyl and pyrazole rings in (VIII) .

Further support is obtained from the ultraviolet spectrum v CH3OH of (VIII) which has a 259 ημ (€. 21 , 300) con- max sistent with the absorption expected for conjugated 1-pheny; -3-substituted pyrazoles. In the l-phenyl-5 -substituted isomer (VII) the bulky tetrahydrothebaine substituent adjacent to the pyrazole nitrogen bearing the phenyl substituent hinders this co-planar conformation, and both the nuclear magnetic resonance and 1CH3OH ultraviolet (VII; 242 mu ( £. 13, 300) , inflection max because of end-absorption interference) spectra are consistent.

The condensation solvents may also determine the predominant isomer (IC or ID) . For example, when acetic acid is used for the condensation of (IIA) with substituted hydrazines, the 1-aryl (or other substituent) 5-pyrazolyl isomers (IC) are generally obtained substantially free of the other isomer (ID) . A modified ■ procedure which produces predominantly the other isomer, the 1-aryl (or other substituent ) -3-pyrazolyl compounds (ID) is illustrated as follows. The 7- ( 2-formyl-l-methoxyvinyl) derivative (IIA) is treated with perchloric acid in methanol, and a keto-ketal (IX) (partial structure only shown) intermediate is presumably formed in situ and condensed, without isolation, with an appropriate arylhydrazine such as phenylhydra-zine.

(IX) (X) The phenylhydrazone (X) (partial structure only shown) is then obtained as a crude intermediate, and is cyclized, without further purification, by heating with dilute hydrochloric acid in acetic acid.

The substituted 7-heterocyclic-7,e-dihydro-6- . (hydroxy or methoxy ) -6, l -endp( etheno or ethano) codides and morphides (IA and IB) of the present invention are active analgesics when measured by the "writhing syndrome test for analgesic activity as described by Siegmund e_t al., Proc. Soc . Exptl . Biol. Med., Vol. 95, p. 729 ( I957) with modifications. This method is based upon the reduction of the number of writhes following the intraperitoneal injection of one mg./kg. of body weight of phenyl-p-quinone in male Swiss Albino mice weighing 15-25 grams per mouse. The syndrome is characterized by intermittent contractions of the abdomen, twisting and turning of the trunk, and extension of the hind legs beginning 3 to 5 minutes after injection of the phenyl-p_-quinone . The test compound is administered orally to groups of two mice each 30 minutes before injection of the phenyl-p_-quinone . The total number of writhes exhibited by each group of mice is recorded for a 3 minute period commencing 15 minutes after injection of the phenyl-p_-quinone . A compound is considered active if it reduces the total number of writhes in two test mice from a control value of approximately 30 per pair to a value of l8 or less per pair. If desired, the results of this test procedure for 10 pairs of mice at each of several dose levels may be used to determine a median effective dose (ED,-n), t defined as the dose required to reduce the number of writhes from about j50 per pair to 18 or less per pair in 50$ of the pairs. In a representative operation, and merely by way of illustration, the following com-pounds of the present invention are active analgesics when tested in this procedure at the indicated oral dose as set forth in Table I below: TABLE I Compound a- ( 5-pyrazolyl ) -6 , 7 , 8, 14-te rahydro-6,14-endoethenothebaine a_ ( l-phenyl-5-pyrazolyl )-6 , 7 * 8 ,14-tetrahydro-6, 14-endoethenothebai 7a- ri-fji-fluorophenyl )-5-pyrazolyl] -6,7,8 , l4-tetrahydro-6, 14-endoeth thebaine 7a- [1-( 4, 6-dimethyl-2-s_-triazinyl )-5-pyrazolyl] -6 , 7 , 8, 14-tetrahydro- -endoethenothebaine 7a-[l-(4, 6-dimethyl-2-pyrimidinyl )-5-pyrazolyl]-6, 7,8, l4-tetrahydro- -endoethenothebaine 7α-Π-ί 2-pyridyl )-5-pyrazolyl] -6, 7*8 , l4-tetrahydro-6, 14-endoethenoth 7a- Γ1-ί 2-quinolyl )-5-pyrazolyl] -6,7,8,14-tetrahydro-6, 14-endoethenot 7α-Γ1-ί 2-benzothiazolyl)-5-pyrazolyl ] -6, 7,8 , 14-tetrahydro-6, 14-endoe thebaine 7a-(2-amino-4-pyriraidinyl )-6, 7,8 , l4-tetrahydro-6, 14-endoethenothebai N-cyclopropylraethyl-7a-( 5-pyrazolyl )-6,7,8 , l4-tetrahydro-6, l4-endoet northebaine hydrochloride N-cyclopropylmethyl-7a- ( 5-isoxazolyl )-6, 7,8 ,14-tetrahydro-6,14-endoe northebaine N-cyclopropylmet yl-7a-(l-phenyl-5-pyrazolyl )-6,7,8 , l4-tetrahydro-6, -endoethenonororipavine citrate N-cyclopropylmethyl-7a-(l-m-chlorophenyl-5-pyrazolyl )-6, 7, 8 , 14-tetra -6, 14-endoethenonororipavine hydrochloride A supplementary procedure is the rat tail-flick method described by F.E. D' Amour and D.L. Smith, J. Pharmacol. Exptl . Thera . , Vol. 72, p. 7k (1941), with modifications. The compounds (generally as hydro-chloride salts in 0.9 saline) are administered sub-cutaneously to groups of 5 rats each. Graded doses are given to several groups of rats. These rats are then individually subjected to a graded intensity heat stimulus from a spot light lamp and a condensing lens focused on the blackened tip of the rat tail.

The characteristic response to this presumably painful heat stimulus is to flick the tail out of the concentrated beam of the heat source. The response time (in seconds) is measured for control and treated groups, and the criterion of analgesia is an approximate 100 increase in response time over controls . Established clinically active analgesics such as meperidine, codeine, morphine, etc., are active in the above test. If desired, a median effective dose (ED^Q) for 100$ increase in re-sponse time over controls may be determined from the results obtained from several graded dose levels. When tested by this procedure using a "high intensity" heat stimulus calibrated to produce an average - 6 second response time in untreated animals (controls), certain compounds of the present invention show this type of analgesic activity as indicated by the appropriate median effective doses as set forth in Table II below: TABLE II Compound 7α_( -isoxazolyl )-6,7,8 , 1 -tetrahydro-e, 14-endo- ethenothebaine 7a-(l-phenyl-5-pyrazolyl)-6,7,8,l4-tetrahydro-6,l4- -endoethenothebaine 7a- [1- (jL-fluorophenyl )-5-pyrazoly1 ] -6, 7, 8 , 14-tetra- hydro-6, 14-endoethenothebaine 7a-[l-( 4,6-dimethyl-.2-s-triazinyl )-5-pyrazolyl] - -6, 7 ,8 , l4-tetrahydro-6, 14-endoethenothebaine 7a- [l-(2-pyridyl)-5-p razolyl] -6,7,8, 1 -tetrahydro- -6, 14-endoethenothebaine N-cyclopropylmethyl-7a-(l-phenyl-5-pyrazolyl )- -6,7,8,l4-tetrahydro-6, l4-endoethenonororipavine citrate N-cyclopropylmethyl-7a- ( 1-m-chloropheny1-5-pyra- zolyl )-6,7,8, l4-tetrahydro-6, 14-endoethenonor- oripavine hydrochloride Additionally, supplementary routine tests known to those skilled in the art may be carried out to assess the importance of side effects frequently associated with the morphine-like analgesics. These in-elude such actions as onset and duration of action, development of tolerance, respiratory depression, addiction liability, relative effects by oral and parenteral administration, and inhibitory effects on the gastrointestinal system.

Other compounds of this invention may show · analgesic antagonist activity when tested against a selected dose of morphine or other morphine-like agents. This antagonist activity may be considered useful as a specific antidote for an overdose of a mor-phine-like agent, or for its non-narcotic analgesic action. Experience has shown that such narcotic antagonists are also capable of relieving pain despite the fact that they are generally inactive in the rat tail-flick procedure (see above), and have little or no addiction hazard; see L.S. Harris and A.K. Pierson, J. Pharmacol. Exptl. Therap., Vol. lkj>, p. 141 (1964). Analgesics which produce satisfactory pain-relief without serious side effects, particularly with regard to the tolerance, habituation and drug dependence of the opiates have been sought for many years. When tested by a procedure similar to that described by Harris and Pierson (above), N-cyclopropylmethyl-7a-(5-pyrazolyl)-6, 7,8, 1 -tetrahydro-6, 14-endoethenonor-thebaine, N-cyclopropylmethyl-7a-(5-isoxazolyl) -6, 7,8,14 tetrahydro-6, 14-endoethenonorthebalne, and N-cyclopropyl methyl-7o ( l-phenyl-5-pyrazolyl ) -6, 7 , 8 , Ik - tetrahydro-6 , 1 -endoethenonororipavine show analgesic antagonist actions when tested against morphine.

In addition, supplementary test procedures such as measuring the elevation of the pain threshold of rat paws inflamed with brewer's yeast may be carried out to confirm the analgesic action of the novel compounds of the present invention. In certain cases, these compounds also show anti -inflammatory activity.

When mixed with suitable excipients or diluents the compounds of this invention can be prepared as pills, capsules, tablets, powders, solutions, suspensions and the like for unit dosage and to simplify administration As analgesics, they will relieve pain by direct action on the nerve centers or by diminishing the conductivity of the sensory nerve fibers . The novel compounds of the present invention may be administered in combination with salicylates such as aspirin and the like .

The novel compounds of the present invention may exist in several isomeric forms such as stereoisomers. It is to be understood that the present invention includes within its scope all such isomeric forms. For example, the codides used as starting materials have several asymmetric carbon atoms, and epimers at the C-7 asymmetric center are possible. Formation of stereoisomers, or epimers, at C-7 is therefore possible in the products of this invention. The nuclear magnetic resonance spectra of these 7a- and 7β-heterocyclic-7J 8-dihydro-6- (hydroxy or methoxy)-6, l -endo(etheno or ethano) codides and morphides are particularly helpful in character izing the mixtures of epimers or the substantially pure steroisomers as obtained from the reaction mixtures or from subsequent purifications and separations. These isomers may then be separated by methods (such as fractional crystallization and partition-chromatography) well known to those skilled in the art.

In accordance with accepted convention, an ot-substituent at the 7-position is behind the plane of the paper whereas a β-substituent as the 7-position is in front of the plane of the paper. This usually represented by a bond for an a-substituen , a bond for a β-substituent, and a bond where both are indicated.

The invention will be described in greater detail in conjunction with the following specific examples .

EXAMPLE 1 Preparation of 7a-(5-isoxazolyl-6,7>8,l - tetra.hvdro-6j l -endoethenothebaine 7a- ( 2-Formyl-l-methoxyvinyl ) -6, J, 8, 14-tetra-hydro-6, 14-endoethenothebaine (500 mg.), hydroxylamine hydrochloride (500 mg.), and acetic acid (10 ml.) are heated on the steam bath for 1 hour. The reaction mixture is diluted with water and the solution is neutralized with sodium bicarbonate. The mixture is extracted with methylene chloride and the extract is washed with water and dried. The residue obtained by evaporation is crystallized from methanol to give 7a- (5-isoxazolyl) -6,7,8, l4-tetrahydro-6,l -endoethenothebaine (4^0 mg., 90$), m- . 172-17 °C.

EXAMPLE 2 Preparation of 7a- (5-pyrazolyl ) -6, 7, 8, 14- -tetrahydro-6, 14-endoethenothebaine 7a- (2-Formyl-l-me hoxyvinyl) -6, 7 , 8, 14-tetra-hydro-6, 14-endoethenothebaine ( 3 g.)> acetic acid (60 ml.), and hydrazine hydrate (3 ml.) are heated on the steam bath for 30 minutes and the crude product is isolated as in Example 1. Crystallization from aqueous methanol gives 7ct- (5-pyrazolyl)-6, 7, 8, l4-tetrahydro-6, 14-endo-ethenothebaine ( 2.8 g., 97% ) , m.p. 120-122°C. with effervescence .

EXAMPLE 3 Preparation of 7a-(l-methyl-5-pyrazolyl)-6, 7j 8,14- -tetrahydro-6, 14-endoethenothebaine 7a- (2-Formyl-l-methoxyvinyl) -6, 7 , 8 , 14-tetra-hydro-6, 14-endoethenothebaine ( 500 mg.), methylhydrazine sulfate ( 250 mg.), and acetic acid (10 ml.) are heated on the steam bath for 30 minutes. The crude product, isolated as in Example 1, is crystallized from aqueous methanol to give 7a-(l-methyl-5-pyrazolyl)-6, 7,8,14-tetrahydro-6, 14-endoethenothebaine (300 mg., 60$), m.p. 203-20 °C.

EXAMPLE 4 Preparation of 7a-(l-phenyl-5-pyrazolyl)-6, 7,8, 14- -tetrahydro-6, 14-endoethenothethebaine 7a- ( 2-Formyl-l-methoxyvinyl ) -6, 7 , 8, 14-tetra-hydro-6, 14-endoethenothebaine (500 mg.), phenylhydrazine hydrochloride ( 250 mg.) and acetic acid ( 10 ml.) are heated on the steam bath for 30 minutes. The mixture is diluted with water and then neutralized with aqeuous sodium bicarbonate. The material which separated is collected, dried via methylene chloride solution followed by evaporation, and crystallized from aqueous methanol to give 7a-(l-phenyl-5-pyrazolyl)-6,7, 8, 14-tetra-hydro-6, 14-endoethenothebalne ( 355 mg., 60 ), m.p. 175-177°C.

EXAMPLE 5 Preparation of 7a-[l-(fi,-fluorophenyl) -5-pyrazolyl]-6,7, 8,l4- -tetrahydro-6,l4-endoethenothebaine 7a- (2-Formyl-l-methoxyvinyl) -6, 7, 8, 14-tetra-hydro-6, 14-endoethenothebaine (500 mg.), £-fluorophenyl-hydrazine ( 195 mg.), and acetic acid (10 ml.) are heated on the steam bath for 1 hour. The crude product is isolated in the same manner as in Example 1 and crystallization from methanol gives la- [1- (^fluorophenyl ) -5-pyrazolyl] -6, 7, 8,1 -tetrahydro-6, 14-endo-ethenothebaine (410 mg., 70$), m.p. 211-213UC.

EXAMPLE 6 Preparation of 7a-[l-(4,6-dimethyl-2-a-triazinyl) -5- -pyrazolyl]-6, 7 8j 1 -tetrahydro-6, 14-Sflflfl.ethenothebaine 7a- ( 2-Formyl-l-methoxyvinyl ) -6, 7, 8, 14-tetra-hydro-6, 14-endoethenothebaine ( 725 mg.), 2-hydrazino-4 , 6-dimethyl-_s-triazine (240 mg.), and acetic acid (15 ml . ) are heated on the steam bath for 1 hour . The crude product is isolated in the same manner as in Example 1 and crystallization from ethyl acetate-n-hexane gives 7a-[l- ( 4,6-dimethyl-2-j3-triazinyl) -5-pyrazolyl1-6, 7 > 8, l4-tetrahydro-6, 14-endoethenothebaine (500 mg., 57$) m.p. l82-l85uC. (inserted at l40uC.).

EXAMPLE 7 Preparation of 7a-[l-(4,6-dimethyl-2-Pyrimidinyl) -5- -pyrazoly1 ] -6, 7 > 8 , 14-tetrahydro-6, 14-endoethenothebaine 7a- ( 2-Formyl-l-methoxyvinyl-6, 7, , 14-tetra-hydro-6, 14-endoethenothebaine (1 g.), 2-hydrazino-4 ,6-dimethylpyrimidine (500 mg.), and acetic acid (20 ml.) are heated under reflux for 1-1/2 hours. The crude product, isolated in the same manner as in Example 1, is heated with water (50 ml.) on the steam bath to remove the excess of 2-hydrazino-4 , 6-dimethylpyrimidine which Is water-soluble. The solid is collected and a solution in methylene chloride is dried and passed through a short column of Magnesol^. Evaporation of the eluate followed by crystallization of the residue from acetone-n-hexane gives 7a-[l-(4,6-dimethyl-2-pyrimidinyl) -5-pyrazolyl ] -6,7, 8, 14-tetrahydro-6 , 14-endoethenothebaine (670 mg., 55#) , m.p. 194-198°C.

EXAMPLE 8 Preparation of 7a- [l-(2-pyridyl) - -pyrazolyl ]- -6, 7, 8, l4-tetrahydro-6, 14-endoethenothebaine 7o (2-Formyl-l-methoxyvinyl ) -6 ,7, 8, 14-tetrahydro-6, 1 -endoethenothebaine (500 mg.), 2-hydrazino-pyridine ( 250 mg.), and acetic acid (10 ml.) are heated under reflux for 1-1/2 hours. The crude product is obtained as in Example 7 and crystallization from acetone-n-hexane gives 7a- [l-(2-pyridyl) -5-pyrazolyl ]-6,7, 8, 14-endoethenothebaine (360 mg., 70#)m.p. 156-158°C.

EXAMPLE 9 Preparation of 7a-[l-(2-quinolyl) -5-pyrazolyl1- -6,7,8,14-tetrah dro-6, 14-endoethenothebaine 7a-(2-Formyl-l-methoxyvinyl)-6,7,8, 14-tetrahydro-6 , 14 -endoethenothebaine (500 mg.), 2-hydrazino-quinoline (188 mg.), and acetic acid (10 ml.) are heated under reflux for 1 hour. The crude product is obtained as in Example 1 and crystallization from methanol gives 7a- [l-(2-quinolyl)-5-pyrazolyl] -6, 7, 8, 14-tetrahydro-6, 14-endoethenothebaine (440 mg.), m.p. 116-120°C.

EXAMPLE 10 Preparation of 7a-[l-(2-benzothiazolyl)-5-pyrazolyl]- -6,7,8, l4-tetrahydro-6, 1 -endoethenothebaine 7 -(2-Formyl-l-methoxyvinyl)-6,7,8,l4-tetra-hydro-6, 14-endoethenothebaine (1 g.), 2-hydrazinobenzo-thiazole (400 mg.), and acetic acid (20 ml.) are heated under reflux for 1 hour. The crude product is obtained as in Example 1 and crystallization from methylene chloride-methanol gives 7a-[l-(2-benzothiazolyl)-5-pyrazolyl ] -6 , 7, 8, 14-tetrahydro-6 , 1 -endoethenothebaine (1.1 g. ), m.p. 209-211°C.

EXAMPLE 11 Preparation of 7a-(2-amino-4-pyrimidlnyl)-6,7,8,l4- -tetrahydro-6, 1 -endoethenothebaine 7a- ( 2-Formyl-l-methoxyvinyl ) -6, 7, 8, 14-tetra-hydro-6, 1 -endoethenothebaine (1 g.), guanidine carbonate (500 mg.), and ethanol (100 ml.) are heated under reflux for 48 hours. The cooled mixture is filtered and solvent is evaporated. The residue is collected with the aid of water and crystallization from aqueous methanol gives 7a- ( 2-amino-4-pyrimidinyl ) -6,7,8, l4-tetrahydro-6,l4-endoethenothebaine (700 mg.; 70$), m.p. 175-178°C.

EXAMPLE 12 Preparation of N-cyclopropylmethyl-7a-(5-pyrazolyl)--6, 7, 8, 14-tetrahydro-6,14-endoethenonorthebaine hydro- chlorlde N-Cyclopropylmethyl-7a- ( 2-formyl-l-methoxy-viny 1) -6, 7 , 8, 14-tetrahydro-6 , 14-endoethenonorthebaine hydrochloride ( 2 g.), hydrazine hydrate ( 2 rnl . ) and acetic acid (40 ml.) are heated on the steam bath for 30 min. The mixture is diluted with water and neutralized with powdered sodium bicarbonate. The mixture is extracted with methylene chloride and the extract is washed with water and dried. Evaporation of solvent gives a gum which is dissolved in dilute hydrochloric acid -(56 ) and the solution is washed ith ether. The aqueous phase is neutralized with powdered sodium bicarbonate and the material which separtes is collected and dried. Crystallization from methylene chloride-methanol-acetone gives N-cyclopropy.lmethyl-7a- ( 5-pyra-zolyl)-6, 7, 8, 14-tetrahydro-6, 14-endoethenonorthebaine hydrochloride (400 mg.), m.p. 303-305 °C. dec. The mother liquor is evaporated and the residue is treated with dilute hydrochloric acid and then with dilute hydrochloric acid and then with sodium bicarbonate as before. The material which separates is collected, washed with acetone, and dried to give a further amount (450 mg.) of product, m.p. 302-305°C, and a total yield of 5 .

EXAMPLE 13 Preparation of N-cyclopropylmethyl-7 - ( 5-isoxazolyl)- 6, 7 , 8,14- etrahydro-6 , 1 -endoethenonorthebaine N-Cyclopropylmethyl-7a- ( 2-formyl-l-methoxy- vinyl ) -6, 7, 8, 14-tetrahydro-6 , 14-endoethenonorthebaine hydrochloride (l g.), hydroxylamine hydrochloride (1 g.), and acetic acid (20 ml.) are heated on the steam bath for 1 hr. After the addition of water, the mixture is neutralized with powdered sodium bicarbonate and extracted with methylene chloride. The extract is washed with water and dried. Evaporation of solvent gives a gum, a solution of which in methylene chloride is passed through a short column of Magnesol^. The eluate is evaporated and the residue crystallized from methanol to give N-cyclopropylmethyl-7a-(5-isoxazolyl)-6,7,8, l4-tetrahydro-6, 14-endoethenonorthebaine (500 mg., 6 ), m.p. 144-146°C.

EXAMPLE 1 Preparation of N-cyclopropylmethyl-7o (5-pyrazolyl) - 6,7,8, 14-tetrahydro-6, 14-endoethenonororipavine N-Cyclopropylmethyl-7ct- (2-formyl-1-methoxyvinyl ) 6, 7j8, l4-tetrahydro-6, 14-endoethenonororipavine (1 g.), hydrazine hydrate (1 ml.), and acetic acid (20 ml.) are heated on the steam bath for 30 min. The mixture is diluted with water and is then basified with ammonium hydroxide. The material which separates is collected, dried, and crystallized from acetone-n-hexane to give -cyclc^¾^^^methyl-7a- (5-pyrazolyl) -6-7,8, l4-tetrahydro-6, 14-endoethenonororipavine (380 mg., 40$), m.p. 198-200°C.

EXAMPLE 15 Preparation of N-cyclopropylmethyl-7a- (5-isoxazolyl) - 6,7,8, l4-tetrahydro-6, 14-endoethenonororipavine N-Cyclopropylmethyl-7o (2-formyl-l-methoxy- vinyl ) -6, 7, 8, l4-tetrahydro-6 , 1 -endoethenonororipavine (1 g.), hydroxylamine hydrochloride (1 g.), and acetic acid (20 ml.) are heated on the steam bath for 1 hr.

The mixture is diluted with water and is then neutralized with aqueous sodium bicarbonate. The precipitated product is extracted into methylene chloride, . and the extract is washed with water and dried. Evaporation oi' solvent gives a gum, a solution of which in methylene chloride is passed through a short column of Magnesol . The eluate is evaporated and the residue collected with the aid of ether. Crystallization from acetone-n-hexane gives N-cyclopropylmethyl-7a-(5-isoxazolyl)-6,7,8, l -tetrahydro-6, 1 -endoethenonororipavine (28θ mg.),, mp 182-184 °C. An additional amount (50 mg.), m.p. 185-l86°C, was obtained from the mother liquor to give a total yield of 3556.

EXAMPLE 16 Preparation of N-cyclo^ri8¾¾methyl-7t-(l-phenyl-5-pyra-zolyl ) -6, 7, 8, l -tetrahydro-6, l -endoethenonorthebaine hydrochloride N-Cyclopropylmethyl-7a- (2-formyl-l-methoxy-vinyl ) -6, 7,8, l -tetrahydro-6, 1 -endoethenonorthebaine (5 S«)j phenyl hydrazine hydrochloride (2.5 g.)> and acetic acid (100 ml.) are heated on the steam bath for 30 min. The mixture is diluted with water and is then basified with ammonium hydroxide. The material which separates is collected and dried via methylene chloride solution. The residue obtained by evaporation of solvent is dissolved in methylene chloride and the solution is passed through a short column of Magnesol . The eluate Is evaporated to give a gum. A portion of this gum ( 500 mg.) is dissolved in methanol, and dilute hydrochloric acid ( 5 ) is added in excess. The solution is extracted with methylene chloride and the extract is dried and evaporated. The residue is collected with the aid of acetone and crystallized from methanol-acetone to give N-cyclopropylmethyl-7a- (l- henyl^-pyrazolyl)^^^, l4-tetrahydro-6, 14-endoethenonorthebaine hydrochloride ( 250 mg.), m.p. 272-274°C. dec. The re-mainder of the above gum is treated in a similar fashion to give further amounts (1.147 g. and 1.243 g-), m.p. 274°C. dec. and m.p. 277°C. dec., respectively, and a total yield of >9%.

EXAMPLE 17 Preparation of N-cyclopropylmethyl-7a- ( l-phenyl-5-pyra-¾olyl) -6, 7 , 8, l4-tetrahydro-6, 14-ejidoethenonororipavine N-Cyclopropylmethyl-7o!- (2-formyl-l-methoxy-vinyl ) -6, 7 , 8, l4-tetrahydro-6, 14-endoethenonororipavine ( 5 . ) i phenylhydrazine hydrochloride (2.5 . ) j and acetic acid (100 ml.) are heated on the steam bath for 30 min. The mixture is diluted with water and is then made basic with ammonium hydroxide. The material which separates is collected and dried via methylene chloride solution followed by evaporation of solvent to give a glass. A solution of this glass in methylene chloride is passed through a short column of Magneso ®r-Evaporation of the eluate gives a gum which crystallizes on the addition of ether, and is collected with the aid of ether to give N-cyclopropylmethyl-7a-(l-phenyl-5-pyrazolyl) -6, 7, 8, l4-tetrahydro-6, 14-endoethenonorori- pavine (2.8 g., K ) , m.p. l84-l86°C. The compound ACH3OH has /' 242 (inflection point; £13,300)- and 289 max (69000).

A hot solution of citric acid (1.5 g.) in ethanol (5 ml.) is added to a hot solution of pyrazole (1.5 g.) in ethanol (15 ml.). N-Cyclopropylmethyl-7a- ( l-phenyl-5-pyrazoly1 ) -6 ,7, 8, 14 -tetrahydro-6 , 14-endo-ethenonororipavine citrate (1.416 g.), m.p. 216°C. dec . , separates on standing for several hours . The mother liquor is warmed and ether is added, when a further amount (4 0 mg.) of product, m.p. 217°C. dec., separates to give a total yield of 98 . The compound v KBr has/tmax 2.93, 3.8 (broad), 5·7½, 5.82 (shoulder), and 6.25 μ,' nuclear magnetic resonance (de-DMS0)^ 7.50 and 6.13 (pyrazole C3 , -H and C41-H, doublets, J3,}4:,=1.8 cps), 5.8 and 5.72 cps), 4.48 (C5-H), 3.08 (Ce-methoxyl), and 2.70 (-CH2-of citrate 2 protons or one mole of citric acid per mole of thebaine derivative).

EXAMPLE 18 Preparation of 7a- (5-isoxazolyl) -6, 7,8, 14- -tetrahydro-6, 14-endoethenooripavine Following the general procedure of Example 1, 7a_(2-formyl-l-methoxyvinyl) -6,7,8, l4-tetrahydro-6, 14-endoethenooripavine is treated with hydroxylamine hydrochloride in acetic acid to give 7a- (5-isoxazolyl ) -6,7,8, 14-te rahydro-6, 14-endoethenoorlpavine .

EXAMPLE 19 Preparation of 7a-(5-pyrazolyl-6,7,8,14- -tetrahydro-6, 14-endoethenooripavlne Following the general procedure of Example 2, 7a- ( 2-formyl-l-methoxyvinyl ) -6 , 7, 8, l4-tetrahydro-6, 14- endoethenooripavine is treated with hydrazine hydrate in acetic acid to give 7a-(5-pyrazolyl)-6,7,8, 14-tetrahydro- 5 6, 14-endoethenooripavine .

EXAMPLE 20 Preparation of 3-acetyl-N-cyclopropylmethyl-7a- (5-iso- xazolyl ) - 6, 7 , 8·, 14-tetrahydro-6 , 14 -endoethenonororipavine Acetylation of N-cyclopr opylmethyl-7a-(5- 10 isoxazolyl)-6,7,8, 14-tetrahydro-6, 14-endoethenonorori- pavine using acetic anhydride in pyridine gives 3- acetyl-N-cyclopropylmethyl-7a- (5-isoxazolyl)-6,7>8i 14-tet- rahydro-6, 14-endoethenonororipavine .

EXAMPLE 21 Preparation o 7a~(5-isoxazolyl)-6,7,8,14- -tetrahydro-6, 14 -endoethenonorthebaine Following the general procedure of Example 1, 7a- ( 2-formyl-l-methox vinyl ) -6, , , 14-tetrahydro- 6, 14-endoethenonorthebaine is treated with hydroxylamine 20 hydrochloride in acetic acid to give 7a-(5-isoxazolyl)- 6,7,8, 1 -tetrahydro-6, 1 -endoethenonorthebaine .

EXAMPLE 22 Preparation of N-allyl-7a-(5-isoxazolyl)-6,7,8, 14- -tetrahydro-6, 14-endoethenonorthebaine 7a-(5-Isoxazolyl)-6,7,8,14-tetrahydro-6,l4- endoethenonorthebaine is treated with allyl bromide in an inert solvent to give N-allyl-7a-(5-isoxazolyl)- 6 , 7, 8, 14-tetrahydro-6, 14-endoethenonorthebaine .

EXAMPLE 23 • 5° Preparation of 7a-(5-isoxazolyl)-N-propyl-6,7J8,14- -tetrahydro-6, 14-endoethenonorthebaine 7a-(5-Isoxazolyl)-6,7,8,l4-tetrahydro-6,l4-endoethenonorthebaine is treated with propyl bromide in an inert solvent to give 7 -(5-isoxazolyl)-N-propyl-6,7,8, l4-tetrahydro-6, 14-endoethenonorthebaine .

EXAMPLE 24 Preparation of 7a- (5-isoxazolyl )-N-phenethyl-6, 7, , 14- -tetrahydro-6, 1 -endoethenonorthebaine 7a-(5-Isoxazolyl)-6,7,8,l4-tetrahydro-6,l4-endoethenonorthebaine is treated with phenethyl chloride in an inert solvent to give 7a- (5-isoxazolyl) -N-phenethyl-6,7*8, 14-tetrahydro-6, 1 -endoethenonorthebaine .

EXAMPLE 25 Preparation of 7a-(5-isoxazolyl)-N-(3-methyl-2-buten-l- yl )-6, 7, 8, 14-tetrahydro-6, 1 -endoethenonorthebaine 7a-(5-Isoxazolyl)-6,7,8,l4-tetrahydro-6, 14-endoethenonorthebaine is treated with 3-methyl-2-buten-1-yl bromide in an inert solvent to give 7a- (5-isoxazolyl ) N-(3-methyl-2-buten-l-yl)-6,7,8,l4-tetrahydro-6,l4-endoethenonorthebalne .

EXAMPLE 26 Preparation of 7a- (5-isoxazolyl )-N-propargyl-6, 7, 8, 14- -tetrahydro-6, 14-endoethenonorthebaine 7a- (5-Isoxazolyl) -6,7,8,14-tetrahydro-6, 14-endoethenonorthebaine is treated with propargyl bromide in an inert solvent to give 7a- (5-isoxazolyl ) -N-propargyl-6,7,8, l4-tetrahydro-6, 14-endoethenonorthebaine .

EXAMPLE 27 Preparation of 7a-(4-ethyl-5-pyrazolyl)-6,7,8, 14- -tetrahydro-6, l4-endoethenothebaine Following the general procedure of Example 2, 7a- ( 2-formyl-l-methoxy-l-butenyl)-6, 7i 8, 14-tetra-hydro-6, 14-endoethenothebaine is treated with hydrazine hydrate in acetic acid to give 7a- ( 4-ethyl-5-pyrazolyl)-6, 7 i 8, 14-tetrahydro-6, 14-endoethenothebaine .

EXAMPLE 28 Preparation of 7a- (5--isoxazolyl)-6, 7, 8, 14- -tetrahydro-6 , 1 -endoethanothebaine Following the general procedure of Example 1, 7a- ( 2-formyl-l-methoxyvinyl ) -6, 7 , 8, l4-tetrahydro-6, 14-endoethanothebain.e is. treated, with hydroxylamine hydrochloride in acetic acid to give 7a- ( 5-isoxazolyl)-6, 7, 8, 14-tetrahydro-6, 14-endoethanothebaine .

EXAMPLE 29 -tetrahydro-6, 1 -endoethenothebaine Following the general procedure of Example 2, 7β- ( 2- ormyl-l-methoxyvinyl ) -6 , 7 , 8 , l4-tetrahydro-6, 14-endoethenothebaine is treated with hydrazine hydrate in acetic acid to give 73- (5-pyrazolyl)-6, 7, 8, 14-tetrahydro-6, 14-endoethenothebaine .

EXAMPLE 30 Preparation of 7a- (5-isoxazolyl) -7, 8-dihydro-6- -hydroxy-6, 14-endoethenocodide " Following the general procedure of Example 1, 7a- ( 2-formyl-l-methoxyvinyl ) -7, 8, -dihydro-6-hydroxy-6 , 14-endoethenocodide is treated with hydroxylamine hydrochloride in acetic acid to give 7a- ( 5-isoxazolyl ) -7 , 8-dihydro-6-hydroxy-6, 14-endoethenocodide .

V.

EXAMPLE 31 Preparation of N-cyano-7a-(5-isoxazolyl)-6, 7,8,14- -tetrahydro-6, 1 -endoethenonorthebaine Following the general procedure of Example 1, N-cyano-7a-(2-formyl-l-methoxyvinyl)-6,7,8,l4-tetra-hydro-6,l4-endoethenonorthebaine is treated with hydroxy-lamine hydrochloride in acetic acid to give N-cyano-7a-(5-isoxazolyl) -6,7,8, l4-tetrahydro-6,l4-endoethenonorthe-baine .

EXAMPLE 32 Preparation of N-cyclopropylmethyl-7a- [1- (m-chlorophenyl) -5-pyrazolyl ) ] -6,7, 8, l4-tetrahydro-6, 14-endoethenonor- oripavine Following the general procedure of Example 17 N-cyclopropylmethyl-7 - (2-formyl-l-methoxyvinyl )-6,78, 14-tetrahydro-6, 14-endoethenonororipavine is treated with m-chlorophenyl hydrazine hydrochloride in acetic acid to give N-cyclopropylmethyl-7a- [1- (m-chlorophenyl) -5-pyrazolyl) ]-6, 7,8, 1 -1etrahydro-6, 14-endoethenonororipavine . The hydrochloride crystallizes from ethanol and has m.p. 28l-282°C. dec. The compound has nuclear magnetic resonance (CDCL3/de-DMS0) 7.'l+8 and 6.08 (pyrazole C3,-H and C4I-H, doublets, J3 , , ,=1.7 cps.)- EXAMPLE 33 Preparation of N-cyclopropylmethyl-7a-[l-(2-pyridyl)-5-pyrazolyl ) ]-6, 7, 8, l4-tetrahydro-6, 14-endoethenonororipavine Following the general procedure of Example 17, N-cyclopropylmethyl-7a- (2-formyl-l-methoxyvinyl) -6, 7,8, 14-tetrahydro-6, 14-endoethenonororipavine is treated with : 2-hydrazinopryidine in acetic acid to give N-cyclo-propylraet yl-7a- [1- ( 2-pyridyl) - -pyrazolyl) ]-6, 7, 8, 14-tetrahydro-6, 1 -endoethenonororipavine . The compound is crystallized from acetone-n-hexane and has m.p. 136-138°C.

EXAMPLE 34 Preparation of N-cyclopropylmethyl-7a-[l-(j3-fluorophenyl-5-pyrazolyl ) ]-6, 7 , 8, 14-tetrahydro-6, 14-endoethenonorori- pavine - N-Cyclopropylmethy1- 7a - ( 2- ormy 1-1-methoxy-vinyl)-6, 7, 8, l4-tetrahydro-6, 14-endoethenonororipavine (1.4 g.), p_-fluorophenylhydrazine hydrochloride (700 mg.), and acetic acid (40 ml.) ,are heated on the steam bath for 1 hr. The cooled mixture is diluted with water and neutralized with dilute ammonium hydroxide . The material which separates is collected and dried. A solution of this material in methylene chloride is passed through a short column of Magnesol ® and evaporation of the eluate followed by crystallization of the residue from acetone-n-hexane gives N-cyclopropylmethyl-7a-[l-(p_-fluorophenyl) -5-pyrazolyl]-6, 7, 8, l4-tetrahydro-6, 14-endoethenonororipavine (I.038 g.), m.p. 151-153UC.

' EXAMPLE 35 Preparation of N-cyclopropylmethyl-7a-(l-phenyl-3-pyra-zolyl) -6, 7, 8, l4-tetrahydro-6, 14-endoethenonororipavine N-Cyclopropylmethyl-7a- ( 2-formyl-l-methoxyvinyl) 6, 7, 8,l4-tetrahydro-6,l4-endoethenonororipavine (1 g.), methanol ( 25 ml.), and perchloric acid (0.4 ml.) are heated under reflux for 1-1/2 hours. Phenylhydrazine ( 1 ml.) is then added and the mixture is heated under reflux for 1 hour. The solution is then added dropwise with stirring, to an excess of aqueous sodium bicarbonate and th dried purification, is heated on the steam bath with acetic acid (5 ml.) and dilute hydrochloric acid (5 ml.; 5$) for 1 hr. This solution is added dropwise, with stirring, to dilute ammonium hydroxide (20$ v/v) and the material which separates is collected and dried. A solution of this material in methylene chloride is passed through a short column of Magnesol* and the eluate is evaporated to give a gum. Citric acid (540 mg.) is added to a solution of this gum in ethanol (5 ml.) and the mixture is heated on the steam bath until solution takes place. This solution is poured into ether with stirring and the material which separates is collected and crystallized from ethyl acetate to give N-cyclopropylmethyl-7a-(l-phenyl-3-pyrazolyl) -6,7,8, l4-tetrahydro-6, 14-endoethenonor oripavine citrate (l4o mg.), m.p. indefinite from 90-l40°C. This compound has nuclear magnetic resonance (de-DMS0) Q.25 and 6.17 (pyrazole C5. -H and C ,-H; doublets, singlet), -CH2-of citrate; 2 protons or one mole of citric acid per mole of thebaine derivative; peaks at The mother liquor from this citrate is evaporated, and the residue is dissolved in a little methanol. This solution is added dropwise, with stirring, to separates is collected and dried. This material (ca. 220 mg.) is subjected to partition chromatography on (R) Celitety545 using the solvent system heptane: ethyl-acetate .methanol iwater (95:5:17:4) . The eluate is moni-tored at 230 χψ. The main peak (Cut 6) is evaporated, and the residue is dissolved in acetone. n-Hexane is then added to turbidity and the solvent allowed to evaporate at room temperature. The residue (100 mg.), m.p. 143-145°C, is collected. This pure isomer has . CH30H 259 ι ( 1,300) and nuclear magnetic reson- max ance <^7.7 and 6.17 (pyrazole C51 -H and C4,-H; doublets, cps), 7.45 (N-phenyl; multiplet), 4.75 (C5-H), and 3.42 ( Ce-methoxyl ) , 2.33 (doublet, J=5-5 cps, EXAMPLE 36 Preparation of N-cyclopropylmethyl-7t-[l-(2,5-dichloro-phenyl)-5-pyrazolyl]-6,7,8, l4-tetrahydro-6, 14-endo- ethenonororipavine A hot solution of 2,5-dichlorophenylhydrazine (500 mg.) in dilute hydrochloric acid (20 ml.; ) is added drop ise with stirring to a hot solution of N-cyclopropylmethyl-7o ( 2-formyl-l-methoxyvinyl ) -6, 7,8, 14-tetrahydro-6 , 14-endoethenonororipavine (1 g.) in dilute hydrochloric acid (10 ml.; $) . After the addition is completed, the reaction mixture is stirred for 20 min., and extracted with methylene chloride (and a little methanol is used to dissolve material adhering to the flask). The extract is shaken with dilute ammonium hydroxide (20$ v/v), then with water, and dried. The dried methylene chloride solution is passed through a short column of Mangesor^ and the column finally washed with ether. The eluate is evaporated and, after crystallization of the residue from acetone-n-hexane, N-cyclopropylmethyl-7a- [1- ( 2,5-dichloropheny1 ) -5-pyrazoly1 ] -6,7,8,l4-tetrahydro-6, 14-endoethenonororipavine (700 mg.), m.p. 161-163°C. (with ef ervescence) is obtained. The compound has nuclear magnetic resonance (CDCl3)^"7. 7 and 6.10 (pyrazole C3,-H and C4 i-H, doublets, J3 t , 4 cps), 4.25 (Cs-H), 3.27 (Ce-methoxyl) .

MM WteteMte WdiUUbfr blel Wliumi kkhJd N6HiU/ EXAMPLE 37 Preparation of N-cyclopropylmethyl-7a- ( 1-pentafluoro-phenyl-5-pyrazolyl ) -6,7,8, 14-tetrahydro-6, 14-endo- ethenonororipavine Following the general procedure of Example 17, N-cyclopropylmethyl-7a- (2-formyl-l-methoxyvinyl)-6,7,8, 14-tetrahydro-6, 14-endoethenonororipavine is treated with penta luorophenylhydrazine hydrochloride in acetic acid to give N-cyclopropylmethyl-7a- (1-pentafluorophenyl-5-pyrazolyl) -6,7,8, 14-tetrahydro-6, 14-endoethenonororipavine. The compound is crystallized from n-hexane and i has m.p. 211-213°C.

EXAMPLE Wl 38 Preparation of N-cyclopropylmethyl-7a-[l-(ja-chlorophenyl) -3- pyrazolylj-6,7,8,, l4-tetrahydro-6, 14-endoethcnonor- oripavine A hot solution of p_-chlorophenylhydrazine hydrochloride (500 mg.) in dilute hydrochloric acid (20 ml.j $) is added dropwise, with stirring, to a hot solution of N-cyclopropylmethyl-7a-(2-formyl-l-methoxy-vinyl ) -6 ,7 , 8 , l4-tetrahydro-6 , l4-endoethenonororipavine (1 g.) in dilute hydrochloric acid (10 ml.; $). The mixture is stirred for 20 min. after the addition is complete and is then extracted with methylene chloride.

The extract is washed with dilute ammonium hydroxide (20$ v/v), water, and then dried. The solution is passed through a short column of Magnesol and the eluate is evaporated to give N-cyclopropylmethyl-7a-[l-(p_-chlorophenyl) -3-pyrazolyl ] -6, 7, 8, l4-tetrahydro-6, 14-endoethenonororipavine as a gum (790 mg.) having i CH30H max 264 n¾u.

EXAMPLE hbl 39 Preparation of N-cyclopropylmethyl-7a-[l-(m-chlorophenyl)-3-pyrazoly1] -6, 7 , 8, 1 -1etrahydro-6, 14-endoethenonor- oripaylne Following the general procedure of Example 9, N-cyclopropylmethyl-7a-( 2-formyl-l-methoxyvinyl ) -6,7,8, l4-tetrahydro-6, l4-endoethenonororipavine is treated with m-chlorophenylhydrazine in dilute hydrochloric acid to give N-cyclopropylmethyl-7a-[l-(m-chlorophenyl)-3-pyrazolyl]-6,7,8,l4-tetrahydro-6,l4- endoethenonororipavine hydrochloride after separation and purification from the 7a-[l-(m-chlorophenyl)-5-pyrazolyl] isomer by partition chromatography. The com- singlet), 5.02 (C5-H), 3.38 ( Ce-methoxyl ) .

EXAMPLE AL/ 40 Preparation of N-cyclopropylmethyl-7a-[l-(jo.-chlorophenyl)-5-pyrazolyl ] -6 , 7, 8, l4-tetrahydro-6, 14-endoethenonororipa- vine Following the general procedure of Example 17, N-cyclopropylmethyl-7a- ( 2- ormyl-l-methoxyvinyl ) -6,7*8, 14-tetrahydro-6, 14-endoethenonororipavine is treated with £-chloropheny1 hydrazine hydrochloride in acetic acid to give N-cyclopropylmethyl-7a-[l-(o-chloro-pheny1 ) -5-pyrazolyl] -6, 7 8, 14-te.trahydro-6, 14-endoethenonororipavine .

EXAMPLE 41 Preparation of N-cyclopropylmethyl-7a-[l-(j3-chlorophenyl)-5-pyrazolyl]-6,7i 8, l4-tetrahydro-6, 14-endoethenonororipa- vine Following the general procedure of Example 17, N-cyclopropylmethyl-7a-( 2-formyl-l-methoxyvinyl) -6,7,8, 14-tetrahydro-6, l4-endoethenonororipavine is treated with p_-chloropheny1 hydrazine hydrochloride in acetic acid to give N-cyclopropylmethyl-7a- [l-(p-chloropheny1 ) -5-pyrazoly1 ] -6, 7 , 8, 1 -tetrahydro-6, 14-endo ethenonororipavine .

EXAMPLE ί>/ 42 Preparation of N-cyclopropylmethyl-7a- [l-(ji-fluorophenyl)-5-pyrazolyl] -6 , 7 , 8,m-tetrahydro-6 , 14-endoethenonororipa- vine Following the general procedure of Example 17, N-cyclopropylmethyl-7a- ( 2-formyl-l-methoxyvinyl )-6, 7,Q,14-tetrahydro-6 , 14-endoethenonororipavine is treated with m-fluorophenyl hydrazine hydrochloride in acetic acid to give N-cyclopropylmethyl-7a- [ 1- (m-fluorophenyl) -5-pyrazolyl]-6,7, 8, l4-tetrahydro-6 , 14-endoetheno-nororipavine .

EXAMPLE N 43 Preparation of N-cyclopropylmethyl-7a- [l-(mj-methoxyphenyl). 5-pyrazolyl] -6, 7, 8, 1 -tetrahydro-6, 14-endoethenonororipa- vine Following the general procedure of Example 17, N-cyclopropylmethyl-7a- ( 2-formyl-l-methoxyvinyl) -6, 7, 8, l4-tetrahydro-6, 14-endoethenonororipavine is treated with m-methoxyphenyl hydrazine hydrochloride in acetic acid to give N-cyclopropylmethyl-7a- [1- (m-methoxyphenyl) -5-pyrazolyl] -6, 7, 8, l4-tetrahydro-6 , 14-endoethenonororipavine .

EXAMPLE & 44 Preparation of N-cyclopropylmethyl-7 x-[l-(m-bromophenyl)-5-pyrazolyl]-6, 7, 8, 14-tetrahydro-6, 14-endoethenonororipavine Following the general procedure of Example 17, N-cyclopropylmethyl-7ct-(2-formyl-l-methoxyvinyl)-6,7, 8, 14- tetrahydro-6, 14-endoethenonororipavine is treated with m-bromophenyl hydrazine hydrochloride in acetic acid to give N-cyclopropylraethyl-7a-[l-(m-bromophenyl) -5-pyrazolyl 1 -6, 7 , 8, 14-tetrahydro-6, 14-endoethenonororipa-vine .

EXAMPLE Affi 45 Preparation of N-cyclopropylmethyl-7a-[l-(ot,a,a-trifluoro- m-tolyl) -5-pyrazolyl]-6, 7, 8, l4-tetrahydro-6, l4-endo- ethenonororipa ine Following the general procedure of Example 4, N-cyclopropylmethyl-7 t-(2-formyl-l-methoxyv'inyl)-6, 7, 8, 14- tetrahydro-6, 14-endoethenonororipavine is treated with α,α, σ-trifluoro-m-tolylhydrazine hydrochloride in acetic acid to give N-cyclopropylmethyl-7a-[l-(a,a, -trifluoro-m- tolyl ) -5-pyrazolyl ] -6, 7, 8, 14-tetrahydro-6 , 14-endoethenono- roripavine .

EXAMPLE HI! 46 Preparation of N-cyclopropylmethyl-7a-[l-(m-tolyl) -5-pyrazolyl ] -6, 7 , 8, 14-tetrahydro-6 , 14-ejidoethenonororipavine Following the general procedure of Example 4, N-cyclopropylmethyl-7a-(2-formyl-l-methox vinyl)-6, 7, 8, 14-tetrahydro-6, 14-endoethenonororipavine is treated with m-tolylhydrazine hydrochloride in acetic acid to give N-cyclopropylmethyl-7a- [ 1- (m-tolyl ) -5-pyrazolyl ] -6,7, 8, 14-endoethenonororipavine .

EXAMPLE ΗβΙ 47 Preparation of N-cyclopropylmethyl-7a-(l-methyl-5-pyra-zolyl ) -6,I, 8, 14-tetrahydro-6 , 14-endoethenonororipavine Following the general procedure of Example , N-cyclopropylmethyl-7o ( -formyl-l-methoxyvinyl ) -6, 7, 8, 14-tetrahydro-6j 1 -endoethenonororipavine is treated with meth lhydrazine hydrochloride in acetic acid to EXAMPLE tBI 48 Preparation of N-allyl-7a- ( l-phenyl-5-pyrazolyl) -6, 7, 8, 14-tetrahydro-6, 14-ejidoethenororipavine Following the general procedure of Example 17 , N-allyl-7a- ( 2-formyl-l-methoxyvinyl ) -6 , 7, 8, 14-tetrahydro-6, 14-endoethenonororipavine is treated with phenylhydra-zine hydrochloride in acetic acid to give N-allyl-7a- ( 1-phenyl-5-pyrazolyl)-6, 7, 8, l4-tetrahydro-6, 14-endoethenor-oripavine .

EXAMPLE 3ί0/ 49 Preparation of N-allyl-7a-[l-(m-chlorophenyl) -5-pyrazolyl]- 6,7, 8 , 1 -tetrahydro-6, 14-endoethenonororipavine Following the general procedure of Example 17, N-allyl-7a- ( 2-formyl-l-methoxyvinyl ) -6, 7, 8, 14-tetrahydro-6, 14-endoethenonororipavine is treated with m-chlorophenyl-hydrazine hydrochloride in acetic acid to give N-allyl-7a- [l-(m-chlorophenyl) -5-pyrazolyl] -6, 7, 8, 14-tetrahydro-6 , 1 -endoethenonororipavine .

EXAMPLE 131 50 Preparation of N- ( 3-methyl-2-buten-l-yl) -7a-(l-phenyl-5-pyrazolyl) -6,7,8, l4-tetrahydro-6, 14-endoethenonororipavine Following the general procedure of Example 17, N- ( 3-methyl-2-buten-l-yl ) -7a- ( 2-formyl-l-methoxyvinyl ) -6, 7, 8, 14-tetrahydro-6, 14-endoethenonororipavine is treated with phenylhydrazine hydrochloride in acetic acid to give N- ( 3-methyl-2-buten-l-yl) -7a-(l-phenyl-5-pyrazolyl ) -6, 7, 8, 14-tetrahydro-6, 14-endoethenonororipavine .

EXAMPLE ffiaf 51 Preparation of N- ( 3-methyl-2-buten-l-yl) -7a-[l-(jD-chloro-phenyl) -5-pyrazolyl]-6, 7, 8,l4-tetrahydro-6,l4-endoetheno Following the general procedure of Example 17, N-(3-methyl-2-buten-l-yl)-7a-(2-formyl-l-methoxy-vinyl)-6,7,8,l -tetrahydro-6,l -endoethenonororipavine is treated with m-chlorophenylhydrazine hydrochloride in acetic acid to give N-(5-methyl-2-buten-l-yl)-7o-[l-(m-chlorop enyl)-5-pyrazolyl]-6,7,8,l --tetrahydro-6,l4-endoethenonororipavine .

EXAMPLE W 52 Preparation of N-cyclobutylmethyl-7 - ( l-phenyl-5-pyrazolyl )- 6,7,8, l4-tetrahydro-6, 14-endoethenonororipavine Following the general procedure of Example 17, N-cyclobutylmethyl-70:- (2-formyl-l-methox vinyl ) -6,7,8, l4-tetrahydro-6, l4-endoethenonororipavine is treated with phenylhydrazine hydrochloride in acetic acid to give N-cyclobutylmethyl-7a-(l-phenyl-5-pyrazolyl)-6,7,8, l4-tetrahydro-6 , 1 -endoethenonororipavine .

EXAMPLE fjW I 53 Preparation of N-cyclobutylmethyl-7a-[l-(m.-chlorophenyl)-5-pyrazolyl]-6, 7,8,l4-tetrahydro-6, 14-endoethenonororipavine Following the general procedure of Example 4, N-cyclobutylmethyl-7a-(2-formyl-l-me hoxyvinyl)-6,7,8, 14-tetrahydro-6, 14-endoethenonororipavine is treated with m-chlorophenylhydrazine hydrochloride in acetic acid to give N-cyclobutylmethyl-7t-[l-(m-chlorophenyl)-Ej-p razolyl] -6.7.8.14- tetrahvdro-6.14-endoethenonorori-pavine .

EXAMPLE t J I 53 Preparation of 7a- (2-formyl-l-methoxyvinyl) -6,7,8, 14- tetrahydro-6, 1 -endoethe othebaine J, A solution of phosgene (20 g.) in methylene chloride (200 ml.) is added rapidly dropwise with stirring to a mixture of dimethyl formamide (200 ml.; dried over molecular sieves) and methylene chloride (600 ml.). The mixture is stirred for a further 15 min-utes after the addition is complete. A solution of 7a-( l,l-dimethoxyethyl)-6,7,8,l4-tetra ydro-6,l4--endo-ethenothebaine (19 g.) in methylene chloride (200 ml.) and pyridine (10 ml.) is then added in a slow stream and the mixture is stirred for 45 minutes. Aqueous sodium acetate (1200 ml.; 5 ) is then added and the mixture is stirred vigorously ' for 30 minutes. If necessary, the mixture is adjusted to pH 8 by the addition of aqueous sodium bicarbonate and the layers are separated. The aqueous layer is washed with methylene chloride and is then made strongly alkaline with sodium hydroxide solution (10%). The mixture is extracted with ether and the extract is washed with water and dried. Evaporation of solvent followed by crystal-lization of the residue from acetone-n-hexane gives 7a-(2-formyl-l-methoxyvinyl)-6,7,8,l -tetrahydro-6Jl4-endoethenothebaine (15-37 g.)> m.p. 152-153 °C. A further amount (1.42 g.) m.p. 150-152°C, is obtained from the mother liquor to give a total yield of 87%.

EXAMPLE 55 Preparation of N-cyclopropylmethyl-7a-(2-formyl-l-methoxy-viny1) -6, 7, 8, 1 -1etrahydro-6, 14-endoethenonorthebaine hydrochloride A solution of phosgene (1 g.) in methylene chloride (10 ml.) is added rapidly dropwise with stirring to a mixutre of dimethylformamide (10 ml.; dried over molecular sieves) and methylene chloride (30 ml.)- The mixture is stirred for a further 15 minutes after the addition is complete. A solution of N-cyclopropylmethyl-7a-(l,l-dimethoxyethyl)-6,7,8,l4-tetrahydro-6,l4-endo-ethenonorthebaine (1 g.) in methylene chloride (10 ml.) and pyridine (0.5 ml.) is then added in a slow stream, and the mixture is stirred at room temperature for 4 minutes. Aqueous sodium hydroxide (60 ml.; $) is then added, 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 by evaporation of solvent is dissolved in dilute hydrochloric acid (5 ), and the solution is washed with ether and extracted with methylene chloride . The extract is dried and evaporated. Acetone is added to cause crystallization and the material is collected with the aid of ether to give N-cyclopropylmethyl-7a- ( 2-formyl-1-methoxyvinyl)-6,7,8, l4-tetrahydro-6, 1 -endoethenonorthe-baine hydrochloride (835 mg.)» m-P- 213 -215 UC.

EXAMPLE $7/ 56 Preparation of 7a-(2-formyl-l-methoxyvinyl)-6,7;8,l4-tetra- hydro-6, 1 -endoethenooripavine Following the general procedure of Example 56, 7a-(l,l-dimethoxyethyl)-6,7,8,l4-tetrahydro-6,l4-endo-ethenooripavine is treated with phosgene-dimethyl-formamide followed by hydrolysis to give 7a- ( 2-formyl-1-methoxyvinyl ) -6, 7, 8, l4-tetrahydro-6 , 1 -endoe thenooripavine .

EXAMPLE 6/8/ 57 Preparation of N-cyclopropylmethyl-7a--(2-formyl-l-methoxy-vinyl)-6,7,8, l4-tetrahydro-6, 14-endoethenonororipavine A solution of phosgene (8.5 g.) in methylene chloride (255 ml.) is added dropwise, with slow stirring, to a mixture of dimethylformamide (85, ml.; dried over molecular sieves) and methylene chloride (255 ml.). Fifteen minutes after the addition was complete, a solution of N-cyclopropylmethyl-7a-(l,l-dimethoxyethyl)-6, 7, 8, l4-tetrahydro-6, 14-endoethenonororipavine (8.5 g.) in methylene chloride (85 ml.) and pyridine (4. ml.) is added in a slow stream, and the mixture is stirred at room temperature for 5 min. Aqueous sodium hydroxide (510 ml.; ) is then added and the mixture is stirred vigorously for 30 min. The layers are separated and the methylene chloride extract is washed with water and dried . Evaporation of solvent gives a gum which solidifies on the addition of water. This material is collected and dried via methylene chloride solution followed by evaporation of solvent to give N-cyclopropylmethyl-7a-(2-formyl-l-methoxyvinyl)-6,7i 8, 14-tetrahydro-6, 14-endoethenonororipavine as a glass (8 g.j quantitative yield) .

EXAMPLE. $ EXAMPLE 66/ 59 Preparation of 7a- ( 2-formyl-l-methoxy-l-butenyl ) - -6,7,8, 14-tetrahydro-6 , 14-endoethenothebalne Following the general procedure of Example 55 > 7a-(l,l-dimethoxybutyl) -6, 7,8, l4-tetrahydro-6, 14-endo-ethenothebaine is treated with phosgene-dimethylformamide followed by hydrolysis to give 7a-(2-formyl-l-methoxy-l-butenyl)-6,7,8, l4-tetrahydro-6, 14-endgethenothebaine .

EXAMPLE $N 60 Preparation of 7a-(2-formyi-l-methoxyvinyl)-6,7j ,l4- -tetrahydro-6, 14-endoethanothebaine Following the general procedure of Example 55, 7a-(1, l-dimethoxyethyl)-6,7,8,l4-tetrahydro-6,l4-endo-ethanothebaine is treated with phosgene-dimethylformamide followed by hydrolysis to give 7 -( 2-formyl-l-methoxyvinyl) -6, 7*8, l4-tetrahydro-6, 14-endoethanothebaine .

EXAMPLE bl2l 61 Preparation of 7P-(2-formyl-l-methoxyvinyl)-6,7,8,l4- -tetrahydro-6, 1 -endoethenothebaine Following the general procedure of Example 5 > 7fi-(l,l-dimethoxyethyl)-6,7,8,l4-tetrahydro-6,l4-endo-ethenothebaine is treated with phosgene-dimethylformamide followed by hydrolysis to give 7β- (2-formyl-l-methoxy-vinyl) -6,7,8, 14-tetrahydro-6, 1 -endoethenothebaine .

EXAMPLE fig/ 62 Preparation of 7a-(2-formyl-l-methoxyvinyl)-7j8- -dihydro-6-hydroxy-6, 14-endoethenocodlde Following the general procedure of Example 55 , 7a- ( 1, 1-dimethoxyethy1 ) - 7 , 8-dihydro-6-hyd roxy-6, 1 -endoethenocodide is treated with phosgene-dimethylfor-mamide followed hydrolysis to give 7a- (2-formyl-l-methoxyvinyl) -7, 8 , -dihydro-6-hydroxy-6, 1 -endoetheno-codide.

EXAMPLE jSA 63 Preparation of N-cyano-7a- (2-formyl-l-methoxyvinyl) - -6, 7 , 8, 14-tetrahydro-6, 14-endoethenonorthebaine Following the general procedure of Example 55 , N-cyano-7a.-(l,l-dimethoxyethyl)-6, 7 , 8, 14-tetrahydro-6, 14-endoethenonorthebaine is treated with phosgene-dimethyl-formamide followed by hydrolysis to give N-cyano-7a-( 2-formyl-l-methoxyvinyl) -6, 7, 8, l4-tetrahydro-6, 14-endoethenonorthebaine .

EXAMPLE 64 Preparation of N-allyl-7a- ( -formyl-l-methoxyvinyl )- -6, 7, 8, l4-tetrahydr,o-6, 14-endoethenonororipavine Following the general procedure of Example 6, N-allyl-7a- ( 1, 1-dimethoxyethyl ) -6, 7, 8, 14-tetrahydro-6, 14-endoethenonororipavine is treated with phosgene-dimethyl-formamide followed by hydrolysis to give N-allyl-7a-(2-formyl-l-methox vinyl)-6, 7 , 8, l4-tetrahydro-6, 14-endoethenonororipavine .

EXAMPLE ££/ / 65 Preparation of 7a- ( 2-formyl-l-methoxyvinyl ) -N- Q-methyl-2-buten-l-yl)-6, 7, 8, l4-tetrahydro-6, 14-endoethenonororipavine Following the general procedure of Example 56 , 7α- (1, 1-dimethoxyethyl) -Ν- (3-methyl-2-buten-l-yl ) - 6, 7j 8, 14-tetrahydro-6, 14-endoethenororipavine is treated with phosgene-dimethylformamide followed by hydrolysis to give 7a- (2-formyl-l-methoxyvinyl )-N-(3-methyl-2-buten-l-yl) -6,7,8, 14-tetrahydro-6, 14-endoethenonororlpa-vine .

EXAMPLE 66 Preparation of N-cyclobutylmethyl-7a-( 2-formyl-l-methoxy vinyl) -6,7, 8, 14 -tetrahydro-6, 14-endoethenonororipavine Following the general procedure of Example 56, N-cyclobuty'lme'th l-7a-(l,l-dimeth'oxyethyl)-6,7,8, i -tetrahydro-6, 1 -endoethenonororipavine is treated with phosgene-dimethylformamide followed by hydrolysis to give N-cyclobutylmethyl-7ct- ( 2-formy1-1-methoxyvinyl ) -6,7,8, 1 -tetrahydro-6, 14-endoethenonororipavine .

EXAMPLE ftg/ 67 Preparation of N-cyclopropylmethyl-7a- ( l-phenyl-5-pyra-zolyl)-6,7i 8, 14-tetrahydro-6, 14-endoethenonororipavine The compound N-Cyclopropylmethyl-7a-( 1-phenyl-5-pyrazolyl)-6,7>8, 1 -tetrahydro-6, 1 -endoethenonororipavine is incorporated into a standard pharmaceutical tablet according to the following formulation.

Per Tablet ingredient For 10, 000 Tablets, g.

N-cyclopropylmethyl- 2 .5 25 7a-( l-phenyl-5-pyrazolyl)-6, 7,8,14-tetrahydro-6, l4-endo-ethenonororipavine Lactose 225 2250 Corn Starch (for mix) 50 500 Corn Starch (for paste) 25 250 Magnesium stearate " 3ϋ7 The active ingredient, 2-amino-5-nitrothiazole, lactose and corn starch for mix are blended together. The corn starch for paste is suspended in water at a ratio of 100 g. of corn starch per 800 ml. of water and heated with stirring to form a paste . The resulting paste is then used to granulate the blended powder. Additional water is used if necessary. The wet granules are passed through a No . 8 screen and dried at 120°F. The dry granules are passed through a No . 16 screen and lubricated with the magnesium st.earate. The granulation is then compressed into tablets (tablet wt . 355 mg.) in a suitable tableting machine . Each tablet contains λ 50 mg. of active ingredient.

EXAMPLE tiy I 68 Preparation of N-cyclopropylmethyl-7a- [l-(m-chlorophenyl)-5-pyrazolyl) ]-6,7> 8, l -tetrahydro-6, 1 -endoethenonorori- pavine The active ingredient N-cyclopropylmethyl-7a-[l-(m-chlorophenyl) -5-pyrazolyl) ] -6, 7,8, l^-tetrahydro-6, l -endoethenonororipavine may be dispensed in hard shell capsules. A formulation found useful for preparing such capsules is as follows: Per Capsule For 1000 Capsules, g.

Ingredient mg.

N-cyclopropylmethyl- 2.5 2.5 7a- [l-(m-chlorophenyl-5-pyrazolyl)]-6,7,8,l -tetrahydro-6, 1 -endo-ethenonororipavine Lactose 90 90 Magnesium stearate 1.5 The active ingredient, lactose and mag-iesium stearate are blended together. The mixture is used to fill hard shell capsules of a suitable size at a fill weight of 9^ mg. per capsule.

EXAMPLE W 69 Preparation of N-cyclopropylmethyl-7a- ( l-phenyl-5-pyra-zolyl)-6,7,8, l4-tetrahydro-6, 14-endoethenonorlpavine The active component, N-cyclopropylmethyl-7 - . (l-phenyl-5-pyrazolyl) -6,7,8, l4-tetrahydro-6, 14-endo-ethenonoripavine may be incorporated into an injectable solution according to the following formulation: Ingredient N-cyclopropylmethyl- 0.1 g. 7a-(l-propyl-5-pyra-zolyl)-6,7,8,l4-tetrahydro-6, 14-endoethenonoripavine Polyethylene Glycol 4000 U.S. P. 4.0 g.

Sodium Chloride U.S. P. 0.90 g.

Benzyl Alcohol, Reagent Grade 0.90 g.

Water for injection qs ad 100.0 ml.

The vehicle is prepared by mixing together all of the above ingredients except N-cyclopropylmethyl-7a- ( 1-phenyl-5-pyrazolyl)-6,7,8, 1 -tetrahydro-6, 14-endoethenonoripavine . The vehicle and active ingredient are rendered sterile by suitable means. A solution of the active ingredient in the vehicle is prepared by dissolving the active ingredient first with a portion of the vehicle and then adding the remaining portion of the vehicle while stirring.

A one ml. dose of this solution therefore, provides 1 rag, of active ingredient.

EXAMPLE yfl/ 70 Preparation of N-cycl0propylmethyl-7 - [1- (m-chlorophenyl-5-pyrazolyl) ]-6,7,8, 14-tetrahydro-6, l4-endoethenonororipa- vine The active component, N-cyclopropylmethyl-7a- [ l-(m-chlorophenyl) -5-pyrazolyl ) ] -6, 7, 8, 14-tetrahydro-6, 14-endoethenonororipavine may be incorporated into an injectable solution according to the following formulation: Ingredient N-cyclopropylmethyl-7a-[ 1- (m-chlorophenyl) -5-pyrazolyl)]-6, 7,8,14-tetrahydro-6, 14-endo-ethenonororipavine 0.1 g.

Polyethylene Glycol 4000 U.S. P. k .0 g.

Sodium Chloride U.S. P. 0.90 g.

Benzyl Alcohol, Reagent Grade 0.90 g.

Water for injection qs ad 100.0 ml.

The vehicle is prepared by mixing together all of the above ingredients except N-cyclopropylmethyl-7a- [ 1- (m- ' chloropheny1 ) -5-pyrazoly1 ) ] -6 , 7, 8, Ik -tetrahydro-6 , 14-endoethenonororipavine. The vehicle and active ingredient are rendered sterile by suitable means. A solution of the active ingredient in the vehicle is prepared by dissolving the active ingredient first with a portion of the vehicle and then adding the remaining portion of the vehicle while stirring.

A one ml. dose of this solution therefore, provides 1 mg. of active ingredient.

Claims (1)

1. Having now particularly described and ascertained the nature our said invention and in what manner the same is to be perrormed, we declare that what we claim is : 1. The process of preparing compounds of the formula: wherein Ri is hydrogen, lower alkyl or lower alkanoyl; Ra is hydrogen, cyano, propargyl, lower alkyl, phenyl lower alkyl, lower alkenyl or lower cycloalkylmethylj R3 is hydrogen or methyl ; Y is etheno or ethano and Q is a moiety of the formulae: wherein R4 is hydrogen or alkyl of from 1 to 7 carbon atoms and Z is -N(R5)-N=, -0-N= or -N=C(NH2)-N= wherein Rs is hydrogen, lower alkyl, phenyl, halophenyl, lov/er alkylphenyl, lower alkoxyphenyl, pyridyl, quinoly, benzothiazolyl, dimethyIpyrimidyl or dimethyl-s_-triazinyl; characterized by contacting a compound of the formula: wherein Ri, R2, R3, R4 and Y are as hereinabove defined and Re is lower alkyl with a heterocycle-forming reagent such as a hydrazine of the formula HN(R5)-NH2, hydroxylamine, guanidine, and salts thereof wherein R5 is as hereinabove defined in a pro tic solvent at a temp erature of from 50°C. to about 125 "C; and recovering the formed product from the reaction mixture. according to claim 1 for compounds 2. . A process /cf/ preparing/ of the formulae: wherein Ri is hydrogen, lower alkyl or lower alkanoyl; R2 is hydrogen, cyano, propargyl, lower alkyl, phenyl lower alkyl, lower alkenyl or lower cycloalkylmethyl; R3 is hydrogen or methyl; R* is hydrogen or alkyl of from 1 to 7 carbon atoms; R5 is hydrogen, lower alkyl, phenyl, halophenyl, lower alkylphenyl, lower alkoxy-phenyl, trifluoromethylphenyl, pyridyl, quinolyl, benzo-thiazolyl, dimethylpyrimidyl or dimethyl-s-triazinyl; and Y is etheno or ethano and the non-toxic acid-addition salts thereof; and the alkali-metal phenolates thereof when Ri is hydrogen. 5. A compound of the formula: wherein Rx is hydrogen, lower alkyl or lower alkanoylj R2 is hydrogen, cyano, propargyl, lower alkyl, phenyl lower alkyl, lower alkenyl or lower cycloalkylmethyl; R3 is hydrogen or methyl; Y is etheno or ethano and Q is a moiety of the formulae: wherein R is hydrogen or alkyl of from 1 to 7 carbon atoms and Z is -N(R5)-N=, -0-N= or -N=C(NH2)= wherein R5 is hydrogen, lower alkyl, phenyl, halophenyl, lower alkylphenyl, lower alkoxy?) pyr'idyl, quinolyl, benzo-thiazolyl, dimethylpyrimidyl or dimethy1-s-triazinyl . wherein Ri is hydrogen, lower alkyl or lower alkanoyl; Rs is hydrogen, cyano, propargyl., lower alkyl," phenyl lower alkyl, lower alkenyl or lower cycloalkylmethyl; R3 is hydrogen or methylj R4 is hydrogen or alkyl of from 1 to 7 carbon atoms; Rs is hydrogen, lower alkyl, phenyl, halophenyl, lower alkylphenyl, lower alkoxy-phenyl, trifluoromethylphenyl, pyridyl, quinolyl, benzo-thiazolyl, dimethylpyrimidyl or dimethyl-s-triazinyl ; and Y is etheno or ethano and the non-toxic acid-addition salts thereofj and the alkali-metal phenolates thereof when Ri is hydrogen. S. HOROWITZ & CO. Agents for Applicants