ES2217852T3 - ANTI-INFLAMMATORY DERIVATIVES OF OXO AND HIDROXI PIRROLIZINAS AND ITS PHARMACEUTICAL APPLICATION. - Google Patents

Abstract

Pyrrolizine compounds of ** formula ** in which either R1 and R2 may be identical or different, being aryl groups or mono or bicyclic aromatic groups, heterocyclic with 1, 2 or 3 heteroatoms which, independently, are selected from N, O and S, where the R1 and R2 groups may optionally be substituted by 1, 2 or 3 groups, which, independently from each other, are selected from alkyl, halogen, CF3, hydroxy, alkoxy, aryloxy and CN, and optionally may be condensed with phenyl or naphthyl; or R3 is H, an alkyl, COOH, COOalkyl, COOAlkPh, COCOOalkyl, CHO or AY group, where A is an alkylene group of 1 to 8 carbon atoms or alkenylene of 2 to 8 carbon atoms, optionally substituted with hydroxyl or alkoxy , Y is COOH, SO3H, OPO (OH) 2, OP (OH) 2, tetrazolyl, COOalkyl, SO3alkyl, CHO or OH; Alk is an alkylene group of 1 to 4 carbons; or R4, R5, R6 and R7, identical or different, are H, alkyl, hydroxyalkyl or alkoxyalkyl; or one of the groups R8 and R9 is H, alkyl, hydroxyalkyl or alkoxyalkyl, and the other is hydroxyl, alkoxy, carboxyl or acyloxy or R8 and R9, together with the carbon atom to which they are attached, form a carbonyl group , as well as their optical isomers, their physiologically tolerable salts and their physiologically easily hydrolysable esters.

Description

Anti-inflammatory derivatives of oxo and hydroxy pyrrolizines and their pharmaceutical application.

The present invention relates to derivatives anti-inflammatory oxo- and hydroxy pyrrolizines, at pharmaceutical compositions containing these compounds and their Pharmaceutical application

Pyrrolizine compounds are already known pharmacologically active that inhibit the 5-lipoxygenase (5-LO) and cyclooxygenases 1 and 2 (Cox-1 and Cox-2). For example, in Arch. Pharm. 319, 231-234 (1986); 318, 661-663 (1985); 318, 663-664 (1985); 319, 500-505 (1986); 319, 749-755 (1986); 327, 509-514 (1994); 330, 307-312 (1997) and in J. Med. Chem. 1987, 30, 820-823 and 1994, 37, 1894-1897 describes pyrrolizine compounds that They have antiflogistic activity. A compound of this type is the 6- (4-chlorophenyl) -7-phenyl-2,3-dihydropyrrolo- [1,2-a] pyrrole ML 3000, see Drugs of the Future, 1995, 20 (10): 1007-1009. This compound suppresses the release of leukotrienes, thromboxanes and prostaglandins. In this structure, the inhibition of the formation of leukotrienes and prostaglandins is balanced and the harmful effects of an action are not observed pure inhibitor on cyclooxygenases 1 and 2 (Cox-1 and Cox-2) that entails a increase in leukotrienes. In all these compounds, position 1 of The pyrrolizine structure is not substituted.

Other pyrrolizine compounds are described in US 5,260,451 and WO 95/32970; WO 95/32971; and WO 95/32972. These compounds have the structural formula

1

A structure of fused diarylpyrrole and a Third acid radical R3 are common to all these compounds. These They are characterized by high lipophilicity, good bioavailability and Average lives of average duration.

According to the general information shown in the WO 95/32970 and WO 95/32971, X may be a group carbonyl Compounds of this type, however, cannot be prepared according to the processes described in WO publications Not mentioned either according to US 5,260,451.

US 3,705,905 describes compounds of formula

two

where X is methylene, α- or β-hydroxyethylene or a carbonyl group and R is a hydroxymethyl group or formyl.

These compounds have antiviral activity, antitumor or immunosuppressive.

Other pyrrolizine compounds that may be used for the treatment of thrombus disorders derived from described in US 4,546,100 and US 4,684,658.

An object of the present invention is provide compounds that, compared to the prior art, they also exert a balanced action at a high level on the two key enzymatic systems of the arachidonic acid cascade, specifically about 5-lipoxygenase and cyclooxygenases

Surprisingly, it has been found that this object is achieved thanks to pyrrolizine compounds that have oxygen functionalities as groups of great polarity in several positions of the ring structure, as is the case with groups carbonyl, hydroxy or alkoxy.

Accordingly, the present invention is refers to pyrrolizine compounds of Formula I

3

in the which

?

R1 and R2 they can be identical or different, being aryl groups or groups mono or bicyclic aromatics, heterocyclic with 1, 2 or 3 heteroatoms that, independently, are selected from N, O and S, where groups R1 and R2 may optionally be substituted by 1, 2 or 3 groups, which, independently of each other, are select from alkyl, halogen, CF 3, hydroxy, alkoxy, aryloxy and CN, and may optionally be condensed with phenyl or naphthyl;

?

R3 is H, a alkyl group, COOH, COOalkyl, COOAlkPh, COCOOalkyl, CHO or A-Y, where

TO

is a group alkylene of 1 to 9 carbon atoms or alkenylene of 2 to 8 atoms carbon, optionally substituted with hydroxyl or alkoxy,

AND

is COOH, SO3H, OPO (OH) 2, OP (OH) 2, tetrazolyl, COOalkyl, SO3 alkyl, CHO or OH;

Alk

is a group alkylene of 1 to 4 carbons;

?

R4, R5, R6 and R7, identical or different, are H, alkyl, hydroxyalkyl or alkoxyalkyl;

?

one of the R8 and R9 groups is H, alkyl, hydroxyalkyl or alkoxyalkyl, and the another is hydroxyl, alkoxy, carboxyl or acyloxy or R8 and R9, together with the carbon atom to which they are attached, they form a group carbonyl,

as well as its optical isomers, its salts physiologically tolerable and its easily hydrolysable esters physiologically

In this case, the salts physiologically tolerable can be acid addition or addition salts of base. In the case of acid addition salts, acids are used inorganic such as hydrochloric acid, sulfuric acid or acid phosphoric, or organic acids such as tartaric acid, acid lactic acid, citric acid, malic acid, mandelic acid, acid ascorbic, maleic acid, fumaric acid, gluconic acid and Similar.

Base addition salts include salts of compounds of Formula I with inorganic bases such as sodium hydroxide or potassium hydroxide or with organic bases such as mono-, di- or triethanolamine.

Easily hydrolysable esters physiologically of the compounds of Formula I are, for example, alkyl esters, pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl

If the compounds according to the present invention they have asymmetric centers, their mixtures are also included racemic and optical isomers (enantiomers, diastereomers).

The expression "alkyl, alkoxy, etc." It includes straight or branched chain alkyl groups, such as methyl, ethyl, n-propyl and isopropyl, n-, i- or t-butyl, n-pentyl, neopentyl, n-hexyl, etc.

Unless otherwise stated, "alkyl" is preferably an alkyl group of 1 to 8 atoms carbon, in particular 1 to 6 carbon atoms and especially an alkyl of 1 to 4 carbon atoms.

"Arilo" is preferably a group Naphthyl and particularly phenyl.

The term "halogen" includes atoms of fluorine, chlorine, bromine or iodine, particularly fluorine or chlorine.

The terms "alkylene" or "alkenylene" represent alkylene or alkenylene groups, branched or linear, preferably 1 to 6 or 2 to 6, particularly from 1 to 4 or from 2 to 4, carbon atoms. The group alkylene and in particular the methylene group is preferred.

The term "acyl" represents an RCO group, where R has the meanings set forth above for "alkyl" and "aryl" preferably. The acetyl group is particularly preferred

The "aromatic heterocyclic group" is, in particular, a 5 and 6 member heterocycle, which may be replaced and condensed in accordance with the above. As Examples cite thiophene, pyrrole, imidazole, thiazole, thiadiazole, furan, oxazole, isoxazole, pyridine, pyrimidine, Benzofuran or quinoline. If the heterocycle is substituted, they appear 1, 2 or 3 substituents that are selected from halogen, CF 3, alkyl of 1 to 8 carbons and alkoxy of 1 to 9 carbons. Is preferably a thiophene or halogen group, in particular a thiophene substituted with chlorine, a furan group, pyridine, benzofuran or a quinoline group.

The substituents of the aryl group are preferably selected from halogens, in particular fluorine or chlorine, and CF 3. If the aryl group is a phenyl ring, the substituents are in position m and / or in position p preferably.

Particularly preferably, R1 and R2 are phenyl, halogen substituted phenyl (substituted with 1 or 2 atoms halogen, in particular chlorine atoms), phenyl substituted with hydroxy or alkoxy (substituted by 1 or 2 hydroxy or alkoxy groups), thienyl or benzofuranyl. Especially, R1 is phenyl and R2 is phenyl substituted by 1 or 2 halogen atoms, in particular atoms of chlorine and / or 1 or 2 hydroxy groups.

The compounds of Formula I in which R3 is COOalkyl, COOAlkphenyl, COCOOalkyl or A-Y, where A and Alk have the meanings indicated above and Y is COOalkyl, SO3 alkyl or OH, are intermediate products that can be used for the preparation of compounds pharmacologically active Formula I. Compounds Pharmacologically active Formula I are those in which R3 is H, alkyl, COOH, CHO or A-Y, where A has the indicated meaning and Y is COOH, SO3H, OPO (OH) 2, PO (OH) 2, CHO or tetrazolyl

Preferably, R3 is H, alkyl, COOH, CHO or A-Y, where A is an alkylene of 1 to 8 carbonosoptionally substituted with OH, and Y is COOH.

The R6 and R7 groups are preferably H and the R4 and R5 groups are preferably alkyl groups, in particular Methyl

A preferred embodiment refers to those compounds of Formula I where R1 is phenyl, R2 is phenyl substituted by 1 or 2 halogen atoms, in particular atoms of chlorine, and / or 1 or 2 hydroxy and / or alkoxy groups; R3 is H, COOH, CHO, CH 2 COOH or CH (OH) COOH; and R4 to R9 have the meanings indicated above.

Another embodiment refers to those compounds of Formula I where one of the groups R4, R5, R6 and R7 is hydroxyalkyl, in particular hydroxymethyl, and the rest of the groups R4, R5, R6 and R7, independently of each other, are H or groups I rent. Preferably R4 is a hydroxyalkyl, in particular hydroxymethyl, R5 is H or alkyl and R6 and R7, independently between Yes, they are H or alkyl. Preferably R1, R2 and R3 have the meanings indicated in the previous paragraph.

Scheme A shows several strategies for introduction of such functional groups that increase the polarity of the pyrrolizine ring skeleton and its derivatives (A-F).

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Scheme TO

4

The compounds according to the present invention can be prepared by oxidation in position 1. The compounds of heading that can be used here are the compounds of Formula II, see Synthesis Scheme 1 below. The compounds of Formula II are prepared according to the processes described by the technique above mentioned above and, in particular in accordance with the processes described in US 5,260,451 and WO95 / 32970, WO 95/32971 and WO 95/32972.

For the preparation of those compounds of Formula I where R3 is COOH, COOalkyl, COOAlkphenyl,
COCOOalkyl or CHO, the compounds of Formula II react in a known manner with N-bromosuccinimide (NBS) in the presence of a free radical initiator, such as azo-bis-isobutyronitrile, in a chlorinated solvent such as carbon tetrachloride. The reaction temperature is selected such that the radical reaction proceeds, for example, at a temperature of 70 to 90 ° C. When 1 molar equivalent of N-bromosuccinimide is used, the compound of Formula III brominated in position 1 is obtained. This compound, in turn, can react with acylates, for example sodium acetate, or alcoholates, such as sodium methylate or ethylate sodium, to provide the corresponding compounds of Formulas Ic and Id. The reactions are carried out in a known manner; The reaction with the acylates takes place in an inert solvent, for example dimethylformamide (DMF), at a temperature of 70 to 90 ° C. The reaction of the compounds of Formula III with alcoholates conveniently takes place in the corresponding alcohol. Alternatively, the compounds of Formula III can react, without being isolated from the reaction mixture, directly with an alcohol to provide the compounds of Formula Id.

As another possibility, a compound of Formula II can react with a molar equivalent of NBS in a solvent chlorinated in aqueous medium to provide a compound of Formula Ia. Using another molar equivalent of NBS then you get a compound of Formula Ib.

In synthesis schemes, "acyl" has the meanings indicated above. R is an alkyl group.

Synthesis Scheme 1

5

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The compounds of Formula I according to the present invention in which R3 is a hydrogen atom are attacked by oxidizing agents especially in the pyrrole core, see Arch. Pharm 318, 661-663 (1985); 663-664 (1985); 319, 231-234 (1986) and 312, 896-907 (1985). The compounds of Formula I in the that R3 is an aliphatic group (for example CH3COOH, CH3) They are attacked especially in this aliphatic substituent. For the preparation of the compounds of Formula I in which R3 is an atom of hydrogen, therefore, the position is first locked reactive 5. As shown in Synthesis Scheme 2, this is performed starting from the compounds of Formula V, whose Preparation is also described in the aforementioned technique, especially in US 5,269,451 and WO 95/32970, WO 95/32971 and WO 95/32972, by introducing a function acyl. For this purpose, a compound of Formula V reacts with trichloromethyl chloroformate in an inert solvent, for example tetrahydrofuran or dioxane, and the ester-derived intermediate reacts with methanol forming a compound of Formula VI. East compound then reacts analogously to the Synthesis Scheme 1 with 2 molar equivalents of N-bromosuccinimide in carbon tetrachloride and in the presence of water to provide a compound of Formula Ie. By decoupling the basic ester as usual, for example using potassium hydroxide in methanol or water, the carboxylic acid of Formula If is obtained. East, in turn, undergoes a decarboxylation at a temperature of 250 at 350 ° C to give a compound of Formula Ig (R3 = H). The compounds of Formula Ig can then be functionalized in position 5 using the usual methods, for example introduction of formyl by the reaction of Vilsmeyer with phosphorus oxychloride in dimethylformamide (DMF) to give a compound of Formula Ix. As alternatively, the ketone group in position 1 of compound Ig can be reduced to an alcohol, for example with complex hydrides such as lithium aluminum hydride. The alcohol function in position 5 it can then be etherified or esterified from the usual way, obtaining the compounds of Formula Ic and Id (R3 = H).

Alternatively, the compound of Formula VI can react with a molar equivalent of N-bromosuccinimide and then with an alcoholate giving a compound of Formula Ii. By dissociation of the ester and decarboxylation, as indicated above, the compounds of Formulas Ij and Ik.

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Synthesis Scheme two

6

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Another way to introduce the acyl function in the Compound of Formula V consists of the route shown in the Scheme of Synthesis 3. A compound of Formula V reacts with chloride of ethyl oxalate in an inert solvent, such as THF or dioxane, to give a compound of Formula XV. This compound, at instead, it oxidizes, as already described in relation to the Scheme of Synthesis 2, with 2 molar equivalents of N-Bromosuccinimide giving a compound of Formula II which, after hydrolysis (dissociation of the basic ester as described above), provides a compound of Formula Im. As alternative possibility, a compound of Formula XV may react with a molar equivalent of N-bromosuccinimide and then with an alcoholate to give a compound of Formula In, which it can be hydrolyzed in the usual way giving the free acid Io. From the compound of Formula I its derivative can be obtained by reduction of the α-ketone group of substituent in position 5 by reduction of Huang-Minlon with hydrazine and a base. Is obtained thus a compound of Formula Ip. The compound reduction of Formula Io using a complex hydride, for example borohydride sodium in water or an aqueous alcohol, provides compound Iq.

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Synthesis Scheme 3

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7

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The oxidizing attack of the N-Bromosuccinimide on substituents aliphatic in position 5 of the compounds according to the present invention, already mentioned above, can be avoided by introduction of protective groups that sterically prevent Access to this position. Thus, the synthesis is carried out from compounds of Formula IV, whose preparation has also been described in the prior art mentioned above and especially in the US 5,260,451 and WO 95/32970, WO 95/32971 and WO 95/32972, following the processes described in the Synthesis Scheme 4. In these processes, a compound of Formula IV is esterified with a highly branched alcohol, such as t-butanol or neopentyl alcohol, in the presence of an activating agent, by example carbonyldiimidazole, in an inert solvent, as per example tetrahydrofuran or dioxane, to provide a compound of Formula XXI. The ester XXI is converted, as described with relation to Synthesis Scheme 2, with 2 molar equivalents of N-Bromosuccinimide in a compound of Formula Ir that, after dissociation of the ester and decarboxylation, provides a compound of Formula Is or It. Alternatively, the ester XXI can react with a molar equivalent of N-bromosuccinimide and then with an alcoholate to provide a compound of Formula Iu. The hydrolysis of the ester and their decarboxylation then provides a compound of Formulas Iv and Iw.

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Synthesis Scheme 4

8

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The introduction of polar groups such as X or R8 = hydroxyl (Scheme A), R8 and R9 = carbonyl and R8 = carboxyl requires a modified synthesis strategy. Such functional groups cannot be introduced subsequently into the hydrocarbon structure of the ring to be fused. The preparation is carried out through suitable precursors that already contain these functional groups, protected by "protecting groups" (Pg = protecting groups).

Scheme B

9

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Synthesis Scheme 5 presents an example of how the application of the methodology described in EP document 0397175 (XXXVII-XXXVIII), from derivatives of tris-hydroxymethylene (XXXIII, X = OH) by introduction selective of a protective group for one of the 3 groups hydroxymethylene, allows to obtain compounds with structure H and J (Scheme B) presenting the corresponding substitution pattern. The compounds of structures H and J are also produced in the form of two optical isomers that, if required, are separated by application of chromatographic techniques or are synthesized in the form of enantiomers pure by using synthetic intermediates diastereomers (acetals or ketals such as R = H, R '= alkyl, aryl etc., or R \ 'R' = alkyl, aryl etc.).

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Synthesis Scheme 5

10

The introduction of a hydroxyl group (Scheme A: structure G (X = OH) in the pyrrolic part of the basic structure of Pyrrolizine provides compounds that are in equilibrium with other tautomeric oxo compounds (XXIX in the Synthesis Scheme 6). In the case of pyrrolizines, these compounds can only be isolated in the form of stable derivatives. They are subject to conversion fast by oxidation with atmospheric oxygen. The scheme of Synthesis 6 describes how, in pyrrolizines that have the structure V, with an appropriate metal, esters can be obtained directly stable of the corresponding hydroxyl derivatives by action of organic peroxides.

Synthesis Scheme 6

eleven

Synthesis Scheme 7 shows that, by treatment with carboxylic acids in the presence of BF 3, substituents in position 5 are also changed (such as the acetic acid side chain R 3 = CH 2 COOH, IIa) by acyl radicals such that acyloxy derivatives of the underlying pyrrolizines (structure XXXII).

Synthesis Scheme 7

12

The compounds according to the present invention produce in vitro and in vivo inhibition of the release of several mediators from the arachidonic acid cascade, particularly of 5-lipoxygenase and cyclooxygenases 1 and 2 and, therefore, have a remarkable anti-inflammatory activity. . Therefore, they are suitable for the treatment of disorders in which the release rate of the eicosanoid mediators responsible for the origin or progressive development of these disorders increases. In particular, the compounds according to the present invention can be used for the treatment of rheumatic type disorders and for the prevention of induced allergic disorders. The compounds according to the present invention are therefore antiphlogistic, analgesic, antipyretic, antiallergic, as well as effective broncholitic and therefore can be used for the prophylaxis of anaphylactic and septic shock and for the treatment of dermatological disorders such as psoriasis, urticaria, rash. acute and chronic allergic and non-allergic origin.

The compounds according to the present invention have great chemical stability, better manageability parenteral, improved enteric bioavailability and more half-lives short

The compounds according to the invention can be administered well as individual therapeutic active compounds or mixed with other therapeutic active compounds. They can be administered as such but, in general, are administered in form of pharmaceutical compositions; that is, as mixtures of these active compounds with pharmaceutical carriers or diluents adequate. The compounds or compositions can be administered orally or parenterally, but preferably administered in oral dosage form.

The nature of the pharmaceutical composition and of the pharmaceutical carrier or diluent depends on the desired form of administration. Oral compositions can be presented, by For example, as tablets or capsules or they may contain usual excipients, such as binders (eg syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone), fillers (e.g. lactose, sugars, corn starch, calcium phosphate, sorbitol or glycine), lubricants (for example magnesium stearate, talc, polyethylene glycol or dioxide silicon), disintegrants (for example starch) or wetting agents (for example sodium lauryl sulfate). Oral preparations liquids can be presented in the form of suspensions, solutions, emulsions, syrups, elixirs or aerosols, etc., whether aqueous or oily, or they can be presented as dry powder for reconstitution with water or another suitable vehicle. The Liquid preparations of this type may contain additives usual as suspending agents, flavorings, diluents or emulsifiers For parenteral administration can be used solutions or suspensions made with pharmaceutical vehicles usual.

The compounds or compositions according to the invention can be administered to mammals (humans and animals) in doses from about 0.5 mg to about 100 mg per kg of weight body and day. They can be administered well in a dose individual or in several doses.

The spectrum of action of the compounds was investigated with the help of the following test systems:

Assay to determine the inhibition of 5-lipoxygenase

As a source of 5-lipoxygenase, They use human granulocytes. Through stimulation with Calcium ionophore A 23187, LTB4 (leukotriene B4) is formed from endogenous arachidonic acid. The granulocytes are isolated and the enzymatic reaction is carried out following the known processes (see Arch. Pharm. Med. Chem. 330, 307-312 (1997)).

The blood, protected against coagulation with heparin, centrifuged in a discontinuous Percoll® gradient and the Granulocyte layer is recovered by pipette. After the Erythrocyte lysis, granulocytes are washed several times and then a specific amount of cells is chosen. TO then the enzymatic reaction begins in the presence or absence of a test substance and after addition of Ca 2+ by calcium ionophore A 23187. The synthesis of Leukotriene stops after 1.5 minutes. The samples are They are separated by centrifugation and the supernatant is diluted. He quantitatively determines the LTB4 through ELISA.

Assay to determine the inhibition of cyclooxygenase-1

In this test the amount of prostaglandin E2 formed from human platelets after of the calcium ionophore addition by ELISA. In this process, platelets are obtained after centrifugation in a Percoll® gradient discontinuous. The enzymatic reaction and the Determination of the metabolites formed are carried out, in principle, as in determining the inhibition of 5-lipoxygenase. There are differences in relation to incubation time In addition, it is necessary to add an inhibitor of thromboxanosintase (see Arch. Pharm. Med. Chem. 330, 307-312 (1997)).

Assay to determine the inhibition of cyclooxygenase-2

COX2 (from sheep placenta) is pre-incubated with the substances to be tested at a temperature of 4 ° C for 10 minutes and then stimulated with arachidonic acid (5 µM) at a temperature of 25 ° C for 10 minutes. The reference used is diclofenac (IC 50 (COX 2) = 3.0 10-6 M). The determination is made in 3 dilutions (10-7, 10-6, 10-5 M), PGE2 concentrations are quantified by ELISA (see Mitchell, J.A. et al. Proc. Nat. Acad. Sci 90: 11693-11697 (1993)).

Partition coefficient determination

The partition coefficient P of the compounds was determined in the n-octanol / water system of compliance with OECD Guideline for Testing Chemicals, [guideline of OECD for chemical testing], No. 117.

The results are shown in Table 1 following.

TABLE 1 IC_ {50} (in \ mumol) and Log P

13

The following examples illustrate the invention without Limit it in any way.

In the examples, the following are used Abbreviations:

THF tetrahydrofuran MeOH methanol NBS N-Bromosuccinimide DMSO sulfoxide from dimethyl DMF dimethylformamide AIBN azobisisobutyronitrile m.p. point of fusion

Example 1 Methyl 6- (4-chlorophenyl) -2,3-dihydro-1-methoxy-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-yl] carboxylate a) Methyl 6- (4-chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-yl] carboxylate

6- (4-Chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1 H -pyrrolizine (10.0 g, 31.1 mmol) prepared according to Laufer et al. (J. Med. Chem. 1994, 37, 1894-1897) and 3.3 g of anhydrous triethylamine in 30 ml of absolute THF. Slowly, drop by drop and at room temperature, a solution of 3.1 g (15.7 mmol) of trichloromethyl chloroformate (diphosgene) in 20 ml of THF is added and the mixture is stirred for 7 hours. Then, 30 ml of MeOH are added. The mixture is stirred again at room temperature for 12 hours. The product precipitates in the form of a pale green solid. The solvent is removed by aspiration and washed with a small amount of MeOH. The mother liquor, mixed with 200 ml of water, provides, after ultrasound treatment (10 minutes), a second fraction of crystals. The fractions thus obtained are purified by stirring with MeOH.

Total yield: 9.94 g (84%), C 23 H 22 ClNO 2, 379.9 g / mol

Melting point: 170 ° C

IR (KBr)

1 / λ (cm -1) = 2945, 1708 (CO ester), 1466, 1406, 1216, 1119, 1098, 831, 777, 702, 696

1 H-NMR (CDCl 3):

δ (ppm) = 7.26-7.11 (m, 7 H, Ph + AA -), 6.99-6.94 (BB ', 2H), 4.14 (s, 2H, CH2), 3.65 (s, 3H, OCH3), 2.84 (s, 2H, H2), 1.31 (s, 6H, C (CH 3) 2)

13 C-NMR (CDCl 3):

δ (ppm) = 161.6 ( C O), 140.3, 134.6, 134.0, 132.4, 132.1, 132.2, 128.5, 128.1, 127.6, 125.5, 117.8, 62.0 (CH 2), 50.7 (O C H 3), 42.4 (C-2), 40.3 (CH 2), 28 , 0 (C ( C H 3) 2)

CHN: calculated C 72.72 H 5.84 N 3.69 found C 72.57 H 5.78 N, 3.64

b) methyl 6- (4-chlorophenyl) -2,3-dihydro-1-methoxy-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-yl] carboxylate

Methyl 6- (4-chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-yl] carboxylate (Example 1a, 4.0 g (10.5 mmol) ) is reacted with 2.3 g (13.0 mmol) of NBS in CCl4 to give [1-bromo-6- (4-chlorophenyl) -2,3-dihydro-2,2-dimethyl-7 -phenyl-1 H -pyrrolizin-5-yl] methyl carboxylate. The intermediate product is not isolated, but reacts directly by adding 30 ml of MeOH. After a few minutes, a solid is deposited. The solvent is removed by aspiration and the solid is washed with a little methanol.

Yield: 3.5 g (81%), C 24 H 24 ClNO 3, 409.9 g / mol

Melting point: 121 ° C

IR (KBr):

1 / λ (cm -1) = 2981, 2956, 2900, 1698, (CO ester), 1455, 1438, 1312, 1217, 1135, 1083, 1012, 780, 703

1 H-NMR (CDCl 3):

δ (ppm) = 7.26-7.04 (m, 9H, 2 Ar.), 4.19-4.14 (m, 3H, 1-H + 3-H 2), 3.66 (s, 3H, COOC H 3), 3.07 (s, 3H, 1-OCH 3), 1.32 (s, 3H, 2-CH 3), 1.21 (s , 3H, 2-CH 3)

13 C-NMR (CDCl 3):

δ (ppm) = 161.6 ( C OOCH 3), 139.3, 134.5, 133.6, 132.4, 131.8, 132.2, 129.4, 128.1, 127 , 6, 126.0, 121.2, 116.2, 83.2, (C-1), 60.1 (C-3), 57.5 (OCH3), 50.9 (COO C H 3), 46.7 (C-2), 27.2, 20.5 (C ( C H 3) 2)

CHN: calculated C 70.32 H 5.90 N 3.42 found C 70.04 H 5.70 N 3.36

Example 2 6- (4-Chlorophenyl) -2,3-dihydro-1-methoxy-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-ylcarboxylic acid

Methyl 6- (4-chlorophenyl) -2,3-dihydro-1-methoxy-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-yl] carboxylate is heated (Example 1b , 3.5 g, 8.5 mmol) in a solution of 3.0 g (53.5 mmol) of KOH in 40 ml of MeOH. The mixture is then cooled and stirred in 400 ml of acidified water at pH 3 with concentrated HCl and extracted three times with 100 ml of diethyl ether each time. The ether extracts are washed with water and dried over Na2SO4. The solution is filtered and concentrated until crystallization begins. The colorless solid is removed by aspiration and dried.

Yield: 2.9 g (86%), C 23 H 22 ClNO 3, 395.9 g / mol

Melting point: 195 ° C

IR (KBr):

1 / λ (cm -1) = 2958, 2895 (acid OH), 1650 (acid CO), 1516, 1492, 1469, 1316, 1136, 1107, 1091

1 H-NMR ([D_ {6}] - DMSO):

δ (ppm) = 7.29-7.11 (m, 7H, Ph + AA '), 7.04-7.00 (BB', 2H), 4.26 (s, 1H, 1-H), 4.12 and 3.98 (m, 2H, AB system, 3-H 2, 2 J = 12.0 Hz), 2.97 (s, 3H, OCH 3), 1.22 (s, 3H, 2-CH 3), 1.14 (s, 3H, 2-CH 3)

13 C-NMR ([D_ {6}] - DMSO):

δ (ppm) = 161.6 (CO), 138.6, 134.3, 134.1, 131.1, 130.2, 132.5, 129.0, 128.1, 127.3, 125 , 9, 120.0, 116.5, 82.4,
(C-1), 59.7 (C-3), 56.8 (OCH 3), 46.2 (C-2), 26.5, 20.3 (C ( C H 3)) _{two})

CHN: calculated C 69.78 H 5.60 N 3.54 found C 69.58 H 5.65 N 3.45

Example 3 6- (4-Chlorophenyl) -2,3-dihydro-1-hydroxy-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-ylcarboxylic acid

6- (4-Chlorophenyl) -2,3-dihydro-1-methoxy-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-yl] carboxylic acid is dissolved (Example 2, 0.50 g, 1.26 mmol) in 10 ml of DMSO having a water content of approximately 10% and then
from the addition of 1.5 ml of concentrated HCl, stir at room temperature for 4 days. Subsequently, the mix
Cla is treated with 30 ml of water. The crystallized is removed from the solvent by aspiration and then collected in 20 ml.
of diethyl ether. The organic phase is washed once with 20 ml of water and dried over Na2SO4. After filtration, the solvent is removed on a rotary evaporator. The solid residue is purified by recrystallization from diethyl ether.

Yield: 0.10 g (21%), C 22 H 20 ClNO 3, 381.9 g / mol

Melting point: 204 ° C

IR (KBr):

1 / λ (cm -1) = 3510 (OH), 2954, 1639 (Acid CO), 1468, 1313, 1139, 1102, 1091, 696

1 H-NMR ([D_ {6}] - DMSO:

δ (ppm) = 7.33-7.05 (m, 9H, 2 Ar.), 5.55 (d, 1H, OH, 3 J = 8.3 Hz), 4.30 (d , 1H, 1-H, 3 J = 8.3 Hz), 4.06 (m, 2H,
3-H 2), 1.17 (s, 3H, 2-CH 3), 1.02 (s, 3H, 2-CH 3)

13 C-NMR ([D_ {6}] - DMSO):

δ (ppm) = 161.7 (CO), 141.5, 134.5, 134.2, 131.1, 130.2, 132.5, 128.6, 128.0, 127.4, 125 , 5, 118.4, 116.0, 74.1
(C-1), 59.5 (C-3), 46.0 (C-2), 26.4, 20.6 (C ( C H 3) 2)

CHN: calculated C 69.20 H 5.28 N, 3.67 found C 68.70 H 5.42 N 3.51

Example 4 Methyl 6- (4-chlorophenyl) -2,3-dihydro-1-oxo-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-yl carboxylate (129)

It is heated at reflux for 3 hours 6- (4-chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-yl] carboxylate methyl (Example 1a, 8.0 g, 21.1 mmol) and 9.4 g (53 mmol) of NBS in 40 ml of CCl4. Then, 2.5 ml of water are added and the mixture is refluxed for an additional 16 hours. The reaction mixture is concentrated to a residual volume of 5 ml and treated with 40 ml of MeOH. It crystallizes at 4 ° C. The pale solid is collected by suction suction from the solvent and dried under vacuum.

Yield: 4.36 g (53%), C 23 H 20 ClNO 3, 393.9 g / mol

Melting point: 233 ° C

IR (KBr):

1 / λ (cm -1) = 2976, 2872, 1707, 1699 (CO ester + ketone), 1464, 1313, 1238, 1147, 1105, 692

1 H-NMR (CDCl 3):

δ (ppm) = 7.30-7.10 (m, 9H, 2 Ar.), 4.46 (s, 2H, 3-H 2), 3.73 (s, 3H, OCH 3), 1.39 (s, 6H, 2-CH 3)

13 C-NMR (CDCl 3):

δ (ppm) = 196.1 (CO), 160.9 (CO), 133.7, 133.3, 132.4, 131.0, 130.2, 132.1, 129.9, 128, 0, 127.9, 127.3, 125.0, 122.0, 59.2 (C-3), 51.6 (O C H 3), 48.8 (C-2), 24, 6 (C ( C H 3) 2)

Example 5 6- (4-Chlorophenyl) -2,3-dihydro-2,2-dimethyl-1-oxo-7-phenyl-1 H -pyrrolizin-5-ylcarboxylic acid

It is heated at reflux for 2 hours 6- (4-chlorophenyl) -2,3-dihydro-1-oxo-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-ylcarboxylate (Example 4, 4 , 4 g, 11.1 mmol) in a solution of 3.0 g (53.5 mmol) of KOH in 40 ml of MeOH. The mixture is allowed to cool and stirred in 600 ml of water. The cloudy solution is brought to pH 3 by adding concentrated hydrochloric acid. The precipitate is filtered off and dried over phosphorus pentoxide in a vacuum desiccator.

Yield: 3.8 g (90%), C 22 H 18 ClNO 3, 379.9 g / mol

Melting point: 284 ° C

IR (KBr):

1 / λ (cm -1) = 2970, 1707 (CO ketone), 1656 (Acid CO), 1518, 1476, 1316, 1302, 1148, 1101, 699

1 H-NMR ([D_ {6}] - DMSO):

δ (ppm) = 7.35-7.31 (AA ', 2H), 7.20-7.10 (m, 7H, Ph + BB'), 4.45 (s, 2H, CH2) ), 1.26 (s, 6H, 2-C H 3} {)

13 C-NMR ([D_ {6}] - DMSO):

δ (ppm) = 196.1 (C-1), 161.0 ( C OOH), 132.9 132.3, 131.8, 131.3, 132.4, 129.6, 127.8, 127.6, 127.0, 129.2, 123.4, 122.9, 58.5 (C-3), 48.3 (C-2), 24.1 (C ( C H 3) _{two})

CHN: calculated C 69.56 H 4.78 N 3.69 found C 69.06 H 4.81 N 3.53

Example 6 6- (4-Chlorophenyl) -2,3-dihydro-2,2-dimethyl-1-oxo-7-phenyl-1 H -pyrrolizine

6- (4-Chlorophenyl) -2,3-dihydro-2,2-dimethyl-1-oxo-7-phenyl-1 H -pyrrolizin-5-ylcarboxylic acid (Example 5, 2.0 g, 5, 3 mmol) until melted for 10 minutes (approximately 290 ° C). As soon as the gas emission is finished, the mixture is allowed to cool and the melt is treated in an ultrasonic bath with MeOH (30 minutes). Then, the solvent is removed by aspiration and the pale brown solid is dried.

Yield: 1.31 g (74%), C 21 H 18 ClNO, 335.8 g / mol

Melting point: 261 ° C

IR (KBr):

1 / λ (cm -1) = 3116 (CH), 2970 (CH), 1684 (CO ketone), 1529, 1350, 1092, 1016, 821, 698, 534

1 H-NMR (CDCl 3):

δ (ppm) = 7.47-7.10 (m, 9 H, 2 Ar.), 7.09 (s, 1H, 5-H), 4.14 (s, 2H, 3-H 2), 1.37 (s, 6H, 2-CH 3)

13 C-NMR (CDCl 3):

δ (ppm) = 194.6 (CO), 133.3, 132.5, 132.0, 129.9, 123.8, 130.0, 129.8, 128.6, 128.1, 127 , 8, 121.9, 56.8 (C-3), 49.7, (C-2), 24.8 (C ( C H 3) 2)

CHN: calculated C 75.11 H 5.40 N, 4.17 found C 73.51 H 5.27 N 4.09

Example 7 6- (4-Chlorophenyl) -2,3-dihydro-1-hydroxy-2,2-dimethyl-7-phenyl-1 H -pyrrolizine

6- (4-Chlorophenyl) -2,3-dihydro-2,2-dimethyl-1-oxo-7-phenyl-1 H -pyrrolizine (Example 6, 0.30 g, 0.9 mmol) is suspended in THF . 0.04 g (1.1 mmol) of LiAlH4 are added and the mixture is heated at reflux for 0.5 hours. It is then allowed to cool and the excess hydride decomposes by adding 10 ml of a saturated NaHCO3 solution. Then 10 ml of 10% NaOH are added and the organic phase is separated. The aqueous phase is extracted 3 times with 10 ml of diethyl ether. The organic extracts are dried over Na2SO4, filtered and concentrated on a rotary evaporator. The product forms a vacuum foam. The residual solvent is removed in vacuo at a temperature of 40 ° C.

Yield: 0.28 g (96%), C 21 H 20 ClNO, 337.9 g / mol

IR (KBr):

1 / λ (cm -1) = 3336 (b), 2958, 2870, 1601, 1525, 1486, 1409, 1173, 1092, 1032, 1012, 833, 767, 700

1 H-NMR (CDCl 3):

δ (ppm) = 7.35-7.12 (m, 9 H, 2 Ar), 6.71 (s, 1H, 5-H), 4.55 (d, 1 H, 1-H, 3 J = 5.3 Hz), 3.96 and 3.64 (AB, 2 H, 3-H 2, 2 J = 10.5 Hz), 1.76 (d, 1 H, 1-OH, 3 J = 5.5 Hz), 1.30 (s, 3 H, 2-CH 3), 1.14 (s, 3 H, 2-CH 3)

13 C-NMR (CDCl 3):

δ (ppm) = 136.9, 135.1, 134.7, 131.2, 129.6, 128.9, 128.28, 128.26, 125.6, 125.7, 117.3, 114.4, (C-5), 75.4 (C-1), 57.5 (C-3), 47.8 (C-2), 26.6, 20.8 (C ( C H_ { 3) 2)

CHN: calculated C 74.67 H 5.97 N 4.15 found C 74.06 H 5.99 N, 3.97

Example 8 6- (4-Chlorophenyl) -2,3-dihydro-2,2-dimethyl-1-oxo-7-phenyl-1 H -pyrrolizin-5-yl carbaldehyde

6- (4-Chlorophenyl) -2,3-dihydro-2,2-dimethyl-1-oxo-7-phenyl-1 H -pyrrolizine (Example 6, 0.30 g, 0.9 mmol) is suspended in 1 ml of DMF. The suspension is cooled to a temperature of 5 ° C; 0.28 g (1.8 mmol) of POCl 3 are added. It is stirred at room temperature for 30 minutes and then heated at a temperature of 80 ° C for 16 hours. The cold reaction mixture is hydrolyzed using 10 ml of 10% sodium hydroxide and extracted twice with 20 ml of methylene chloride. The organic extracts are washed three times with 40 ml of water, dried over Na2SO4, filtered and concentrated on a rotary evaporator. The crude product is recrystallized from ethanol.

Yield: 250 mg (76%) C 22 H 18 ClNO 2, 363.8 g / mol

Melting point: 185 ° C

IR (KBr):

1 / λ (cm -1) = 2962, 2868, 1716, (CO aldehyde), 1662, (CO ketone), 1514, 1458, 1406, 1381, 1118, 1014, 845, 746, 723

1 H-NMR (CDCl 3):

δ (ppm) = 9.64 (s, 1 H, CHO), 7.38-7.19 (m, 9 H, 2 Ar.), 4.49 (s, 2 H, 3-H 2), 1.39 (s, 6 H, 2-CH 3)

13 C-NMR (CDCl 3):

δ (ppm) = 196.9 (CO), 181.7 (CHO), 136.8, 134.3, 130.5, 130.3, 129.3, 124.1, 131.9, 129, 7, 128.9, 128.2, 127.6, 58.6 (C-3), 49.2 (C-2), 24.6 (C ( C H 3) 2)

CHN: calculated C 72.63 H 4.99 N 3.85 found C 72.34 H 5.22 N 3.80

Example 9 T-Butyl 1-Acetoxy-6- (4-chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-ylacetate a) 6- (4-Chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-t-butyl acetate

6- (4-Chlorophenyl) -2,3-dihydro-1-hydroxy-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-yl] acetic acid (ML3000, 10.0 g, 26) is dissolved , 3 mmol), prepared according to Laufer et al. (J. Med. Chem. 1994, 37, 1894-1897), in 40 ml of absolute THF and treated with 5.1 g (31.5 mmol) of carbonyldiimidazole. The mixture is stirred at room temperature for 30 minutes until the imidazole derivative precipitates, then 80 ml of t-butanol are added and the mixture is heated at 100 ° C with water separating. As soon as the THF has been fully distilled, the reaction mixture is heated at 110 ° C for another 7 days. It is then allowed to cool and stirred with 80 ml of diethyl ether or MeOH. The crystallized is released from the solvent by aspiration and drying. Additional crystallization can be obtained from the mother liquor by concentration in a rotary evaporator and precipitation with MeOH.

Yield: 8.0 g (70%), C 27 H 30 ClNO 2 436.0 g / mol

Melting point: 168 ° C

IR (KBr):

1 / λ (cm -1) = 2954, 2870, 1728, (CO ester), 1487, 1379, 1163, 1151, 1097, 822, 700

1 H-NMR (CDCl 3):

δ (ppm) = 7.27-7.03 (m, 9 H, 2 Ar.), 3.75 (s, 2 H, CH 2), 3.41 (s, 2 H, CH_ { 2), 2.84 (s, 2 H, CH 2), 1.47 (s, 9 H,
C (C H 3) 3), 1.29 (s, 6 H, 2-CH 3)

13 C-NMR (CDCl 3):

δ (ppm) = 170.1 (CO), 136.1, 134.8, 133.9, 131.5, 131.6, 128.2, 128.1, 128.0, 124.6, 118 , 4, 114.6, 81.2,
(O C (CH3) 3), 58.3 (CH2), 43.3 (C-2), 40.5 (CH2), 32.9 (CH_ { 2), 28.1 (OC ( C H 3) 3), 28.0 (C ( C H 3) 2)

CHN: calculated C 74.38 H 6.94 N 3.21 found C 73.99 H 6.90 N 3.21

b) 1-Bromo-6- (4-chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-yl t-butyl acetate

T-Butyl 6- (4-chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-ylacetate acetate (Example 9a, 5.0 g, 11.5 mmol) and NBS (2.2 g, 12.4 mmol) with 50 ml of CCl4 and an AIBN spatula tip. The reaction mixture is heated at 50 ° C for 45 minutes. After cooling, the succinimide is filtered off and the solvent is removed in vacuo.

Yield: 5.6 g (95%) C 27 H 29 BrClNO 2; 514.9 g / mol

IR (KBr):

1 / λ (cm -1) = 2968, 2931, (s, aliphatic CH), 1730 (s, width, CO, ester), 1466, 1367, 1147, 1099, 833, 787, 770 ( s,
C-Br)

1 H-NMR (CDCl 3):

δ (ppm) = 7.30-7.12 (m, 7 H, Ph + AA '), 7.11-7.06 (BB', 2 H), 5.15 (s, 1 H, 1 -H), 3.81 (s, width, 2 H, 3-H 2), 3.41 (s, 2 H, C H 2 COOR), 1.48 (s, 9 H, C (C H 3) 3), 1.35 (s, width, 6 H, 2 CH 3)

13 C-NMR (CDCl 3):

δ (ppm) = 169.5 (CO), 134.8, 133.9, 133.5, 132.0, 131.7, 128.9, 128.3, 128.1, 125.6, 124 , 3, 121.7, 118.0, 81.6, (O C (CH 3) 3), 60.8 (C-1), 55.4 (CH 2), 49 , 4 (C-3), 32.9 (CH 2), 28.8 (OC ( C H 3) 3), 25.9 (C ( C H 3) two})

c) 1-Acetoxy-6- (4-chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-yl t-butyl acetate

T-Butyl 1-Bromo-6- (4-chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-ylacetate acetate (Example 9b, 1.15 g , 2.23 mmol) with 0.5 g of potassium acetate, 10 ml of absolute diethyl ether and 3 drops of acetic acid and the mixture is heated at reflux for 3 hours. It is then allowed to cool, the inorganic salts are removed by filtration and the ether solution is concentrated on a rotary evaporator. In a residual volume of approximately 5 ml, 10 ml of hexane are added. After crushing, the product precipitates and is removed from the solvent by aspiration.

Yield: 0.74 g (65%) C 29 H 32 ClNO 4; 494.0 g / mol

Melting point: 81 ° C

IR (KBr):

1 / λ (cm -1) = 2972, 1728, (CO ester), 1368, 1246, 1149, 1014, 833, 708

1 H-NMR (CDCl 3):

δ (ppm) = 7.24-6.99, (m, 9 H, 2 Ar.), 5.92 (s, 1 H, 1-H), 3.92 and 3.75 (2 H, AB, 3-H 2, 2 J = 10.4 Hz), 3.43 (s, 2 H, C H 2 COOR), 2.09 (s, 3 H, OC H 3), 1.48 (s, 9 H, OC (C H 3) 3), 1.25 (s, 3 H, 2-CH 3), 1.21 (s, 3 H, 2-CH 3)

13 C-NMR (CDCl 3):

δ (ppm) = 170.3 (CO), 169.7 (CO), 134.7, 134.1, 131.8, 130.8, 131.7, 128.6, 128.2, 128, 0, 125.5, 124.3, 120.1, 118.6, 81.5 (O C (CH 3) 3), 76.3 (C-1), 56.5 (C -3), 47.6 (C-2), 32.8 ( C H 2 COOR), 28.1 (OC ( C H 3) 3), 26.6 (OCH 3 }), 21.0, 20.9 (CH 3)

CHN: calculated C 70.50 H 6.53 N 2.84 found C 70.83 H 6.71 N 2.81

Example 10 1-Acetoxy-6- (4-chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-yl-2-oxoacetate ethyl a) Ethyl 1-bromo-6- (4-chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-yl-2-oxoacetate

Ethyl 6- (4-chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-yl] -2-oxoacetate (9.82 g, 23.3 mmol), prepared in accordance with the literature, in 50 ml of CCl4. Then 4.70 g (26.4 mmol) of NBS and a spatula tip azoisobutanonitrile (AIBN) are added and the mixture is heated at reflux for 4 hours. After cooling the reaction mixture, the succinimide is removed by filtration and the clear solution is concentrated on a rotary evaporator. The residue is crystallized from diisopropyl ether.

Yield: 8.9 g (76%), C 25 H 23 BrClNO 3, 500.8 g / mol

Melting point: 167 ° C

IR (KBr):

1 / λ (cm -1) = 2966 (CH), 1740 (CO ester), 1630 (COα-ketone), 1446, 1433, 1257, 1068, 1018, 851, 696

1 H-NMR (CDCl 3):

δ (ppm) = 7.30-7.13 (m, 9 H, 2 Ar.), 5.00 (s, 1 H, 1-H), 4.34 and 4.14 (2 H, AB , 3-CH 2, 2 J = 12.5 Hz), 3.64 (m, 2 H, ABX 3, OC H 2, 2 J = 10.8 Hz, 3 J = 7.3 Hz), 1.51 (s, 3 H, 2-CH 3), 1.28 (s, 3 H, 2-CH 3), 1, 08 (t, 3 H, OCH 2 C H 3, 3 J = 7.2 Hz)

13 C-NMR (CDCl 3):

δ (ppm) = 177.4, 164.1 (CO), 143.3, 135.4, 134.0, 132.4, 131.7, 132.2, 129.0, 128.3, 128 , 2, 126.8, 122.9, 120.5, 61.9, (CH2), 59.0 (CH2), 54.9 (C-1), 48.3 (C -2), 26.4, 24.9 (C ( C H 3) 2), 13.5 (OCH 2 C H 3)

CHN: calculated C 59.96 H 4.63 N 2.80 found C 59.95 H 4.64 N 2.74

b) Ethyl 1-acetoxy-6- (4-chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-yl-2-oxoacetate

Ethyl 1-bromo-6- (4-chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-yl-2-oxoacetate
(Example 10a, 10.0 g, 20 mmol) in 50 ml of DMF. After the addition of potassium acetate (5.0 g, 51 mmol), the mixture is heated at a temperature of 80 ° C for 2 hours. Then, the cooled reaction mixture is poured onto ice and extracted with 200 ml of diethyl ether. The ether phase is separated, washed twice with 150 ml of water, dried over Na2SO4, filtered and concentrated on a rotary evaporator.

A mixture of ethyl 1-acetoxy-6- (4-chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-yl-2-oxoacetate and 2- [6- (4-Chlorophenyl) -2,3-dihydro-1-hydroxy-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-yl] -2-ethyl oxoacetate.

Yield: 6.9 g (75%) of a mixture that It contains variable proportions of the two components. The component separation by column chromatography (silica gel 60, ether / cyclohexane 1: 1) sample:

2- [1-Acetoxy-6- (4-chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-yl] -2-C27 ethyl oxoacetate H_26 ClN
O 5, 480.0 g / mol

Melting point: 142 ° C

IR (KBr):

1 / λ (cm -1) = 2970 (CH), 1747 (CO ester), 1624 (COα-ketone), 1448, 1427, 1227, 1084, 1018, 733, 696

1 H-NMR (CDCl 3):

δ (ppm) = 7.29-6.91 (m, 9 H, 2 Ar.), 5.95 (s, 1 H, 1-H), 4.32 and 4.24 (2 H, AB , 3-H 2, 2 J = 12.4 Hz), 3.70-3.55 (m, 2 H, ABX 3, OCH 2), 2.03 (s, 3 H, OCH 3), 1.30 (s, 3 H, 2-CH 3), 1.22 (s, 3 H, 2-CH 3), 1.07 (t, 3 H, OCH 2 C H 3, 3 J = 7.1 Hz)

13 C-NMR (CDCl 3):

δ (ppm) = 177.4 (COα-ketone), 169.8 (CO), 164.1 (CO), 140.8, 135.5, 133.9, 132.3, 131.8 , 128.9, 128.3, 121.3, 132.1, 128.8, 128.2, 128.1, 126.7, 75.0 (C-1), 61.8 (CH2) ), 60.4 (CH 2), 46.7 (C-2), 26.4 (CO C H 3), 20.8, 20.6 (CH 3), 13.5 (OCH 2 C H 3)

CHN: calculated C 67.57 H 5.46 N 2.92 found C 67.48 H 5.48 N 2.89

Example 11 6- (4-Chlorophenyl) -2,3-dihydro-1-hydroxy-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-yl-2-oxoacetate ethyl

After column chromatography of the Example 10b:

C 25 H 24 ClNO 4, 438.0 g / mol

Melting point: 193 ° C

IR (KBr):

1 / λ (cm -1) = 3520 (OH), 2958 (CH), 1730 (CO ester), 1622 (COα-ketone), 1450, 1425, 1269, 1076, 1016, 737, 700

1 H-NMR (CDCl 3):

δ (ppm) = 7.29-7.12 (m, 9 H, 2 Ar.), 4.64 (d, 1 H, 1-H, 3 J = 5.8 Hz), 4 , 29 and 4.23 (2H, AB, 3-H 2, 2 J = 9.8 Hz), 3.75-3.50 (m, 2 H, ABX 3, OCH_ { 2), 1.96 (d, 1 H, OH, 3 J = 5.8 Hz), 1.32 (s, 3 H, 2-CH 3), 1.20 (s, 3 H, 2-CH 3), 1.07 (t, 3 H, OCH 2 C H 3, 3 J = 7.2 Hz)

13 C-NMR (CDCl 3):

δ (ppm) = 177.5 (COα-ketone), 164.3 (CO ester), 144.6, 135.5, 133.9, 132.8, 132.0, 132.2, 129 , 0, 128.4, 128.2, 126.6, 122.0, 120.8, 75.1 (C-1), 61.8 (CH 2), 60.0 (CH 2) ), 46.9 (C-2), 26.4 (C ( C H 3) 2), 20.5 (C ( C H 3) 2), 13.5 (OCH 2 C H 3)

Example 12 6- (4-Chlorophenyl) -2,3-dihydro-1-hydroxy-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-ylacetic acid

T-butyl 1-acetoxy-6- (4-chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-ylacetate acetate (Example 9c, 1.00 g) , 2.0 mmol) in 10 ml of MeOH. 0.5 g of KOH are added and the mixture is heated to reflux until the intermediate precipitate formed has dissolved. It is then allowed to cool and stirred in 600 ml of water. The cloudy solution is brought to pH 3 using concentrated HCl. It is extracted three times using 100 ml of diethyl ether each time. The ether extracts are washed twice with water and dried over Na2SO4, filtered and concentrated on a rotary evaporator. A mixture of 6- (4-chlorophenyl) -2,3-dihydro-1-hydroxy-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-ylacetic acid and 2- [6- ( 4-chlorophenyl) -2,3-dihydro-1-methoxy-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-yl] acetic acid (see Example 16).

Alternative synthesis (6- (4-chlorophenyl) -2,3-dihydro-1-hydroxy-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-ylacetic acid)

A mixture which in turn contains a 1: 2 mixture of 2- [1-acetoxy-6- (4-chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5 -yl] -2-ethyl oxoacetate and 2- [6- (4-chlorophenyl) -2,3-dihydro-1-hydroxy-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-yl] Ethyl -2-oxoacetate (from Example 10b, 1.50 g, 3.31 mmol) is suspended in 15 ml of diethylene glycol, treated with 1.3 ml of hydrazine hydrate (80%) and heated at 80 ° C for one hour . It is then allowed to cool and 2.5 g of KOH are added. It is then heated at a temperature of 130 ° C for one hour and at a temperature of 160 ° C for 2 hours. After cooling, it is diluted with 30 ml of water and brought to pH 2 using concentrated HCl and extracted three times with 30 ml of diethyl ether. The organic extracts are washed twice with 50 ml of water, dried over Na2SO4, filtered and concentrated on a rotary evaporator until a residual volume of 50 ml is obtained. Approximately 20 ml of hexane is added and the mixture is evaporated until crystallization begins. The crystallized is removed by aspiration and the solution is concentrated again. In this way several crystallization fractions are obtained. The latter crystallized contain the compound sought.

Yield: 0.07 g (6%) C 23 H 22 ClNO 3, 395.9 g / mol

IR (KBr):

1 / λ (cm -1) = 3421 (OH), 2958, 2926, 2870 (OH), 1730 (acidic CO), 1485, 1090, 1012, 831, 700

1 H-NMR (CDCl 3):

δ (ppm) = 7.28-7.06 (m, 9 H, 2 Ar.), 4.61 (s, 1 H, 1-H), 3.91, 3.68 (2 H, AB , 3-H 2, 2 J = 10.4 Hz), 3.58 (2 H, AB, C H 2 COOH), 1.31 (s, 3 H, 2-CH_ {3}, 1.15 (s, 3 H, 2-CH3)

Example 13 6- (4-chlorophenyl) -2,3-dihydro-1-methoxy-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-tert-butyl acetate

T-Butyl 1-Bromo-6- (4-chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-yl] acetate (Example 9b, 1, 15 g, 2.23 mmol) in 10 ml of MeOH. After a few minutes, a solid is deposited. The solvent is removed by aspiration and the solid is washed with a small amount of MeOH.

Yield: 0.73 g, (70%), C 28 H 32 ClNO 3, 466.0 g / mol

Melting point: 140 ° C

IR (KBr):

1 / λ (cm -1) = 2881, 1728, (CO ester), 1153, 1369, 1342, 1214, 1089, 827, 746, 698

1 H-NMR (CDCl 3):

δ (ppm) = 7.25-7.08 (m, 9 H, 2 Ar.), 4.22 (s, 1 H, 1-H), 3.88, 3.65 (2 H, AB , 3-H 2, 2 J = 10.3 Hz), 3.43 (s, 2 H, C H 2 COOR), 3.09 (s, 3 H, OCH 3 ), 1.45 (s, 9 H, OC (C H 3) 3), 1.32 (s, 3 H, 2-CH 3), 1.20 (s, 3 H, 2-CH 3)

13 C-NMR (CDCl 3):

δ (ppm) = 169.7 ( C O), 135.9, 134.5, 133.3, 131.5, 131.7, 129.1, 128.1, 128.0, 125.3, 123.7, 119.3, 118.9, 83.5
(C-1), 81.3 (O C (CH 3) 3), 56.8 (O C H 3), 56.4 (C-3), 47.7 (C -2), 32.9 (C H 2 COOR), 28.0 (OC ( C H 3) 3), 27.3, 20.8 (C ( C H 3) )_{two})

CHN: calculated C 72.17 H 6.92 N 3.01 found C 71.38 H 6.85 N 2.99

Example 14 6- (4-Chlorophenyl) -2,3-dihydro-1-methoxy-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-yl-acetic acid

T-Butyl 6- (4-chlorophenyl) -2,3-dihydro-1-methoxy-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-ylacetate acetate (Example 13, 1.00 g) , 2.14 mmol) in 10 ml of MeOH. 0.5 g of KOH are added and the mixture is heated at reflux for two hours. Allow to cool and stir in 600 ml of water. The cloudy solution is brought to pH 3 using concentrated HCl. It is extracted three times with 100 ml of diethyl ether each time. The ether extracts are washed twice with water and dried over Na2SO4. The solution is filtered and concentrated in a rotary evaporator until crystallization begins. The colorless solid is removed from the residual solvent by aspiration and dried.

Yield: 0.66 g (75%), C 24 H 24 ClNO 3, 409.9 g / mol

Melting point: 168 ° C

IR (KBr):

1 / λ (cm -1) = 3034 (CH), 2966, 2884 (OH), 1716 (Acid CO), 1092, 1456, 1225, 1206, 1016, 697

1 H-NMR ([D_ {6}] - DMSO):

δ (ppm) = 7.34-7.28 (m, 2 H, AA '), 7.25-7.02 (m, 7 H, Ph + BB'), 4.23 (s, 1 H , 1-H), 3.71 (s, 2 H, C H 2 COOH), 3.55 and 3.41 (2 H, AB; 3-H 2, 2 J = 16.8 Hz), 2.92 (s, 3 H, OCH 3), 1.21 (s, 3 H, 2-CH 3), 1.12 (s, 3 H, 2-CH_ {3})

13 C-NMR (CDCl 3 / [D 6] - DMSO):

δ (ppm) = 172.4 ( C O), 135.9, 134.4, 133.4, 131.2, 131.6, 129.0, 128.0, 127.96, 125.2, 123.3, 119.3, 118.6, 83.4 (C-1), 56.9 (O C H 3), 56.4 (C-3), 47.5 (C-2) , 31.4 ( C H 2 COOH), 27.3, 20.8 (C ( C H 3) 3)

CHN: calculated C 70.33 H 5.90 N 3.42 found C 69.67 H 5.90 N 3.36

Example 15 6- (4-Chlorophenyl) -2,3-dihydro-1-hydroxy-2,2,5-trimethyl-7-phenyl-1 H -pyrrolizine

6- (4-Chlorophenyl) -2,3-dihydro-1-methoxy-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-ylacetic acid is suspended (Example 14, 0.50 g, 1, 22 mmol) in a mixture of 5 ml of DMSO and 1 ml of water and heated at 90-100 ° C for four hours. After cooling the reaction mixture, 30 ml of diethyl ether are added, the aqueous phase is separated and the ether solution is washed three times with 50 ml of water. After drying over Na2SO4 and filtration, the solution is concentrated in vacuo. The residue crystallizes from cyclohexane.

Yield: 0.26 g (60%), C 22 H 22 ClNO, 351.9 g / mol

Melting point. 133 ° C

IR (KBr):

1 / λ (cm -1) = 3302 (OH), 2956, 2906, 1486, 1381, 1054, 999, 831, 732, 699

1 H-NMR (CDCl 3):

δ (ppm) = 7.26-7.11 (m, 7 H, Ph + AA '), 7.09-7.05 (2 H, BB'), 4.57 (d, 1 H, 1 -H, 3 J = 5.1 Hz), 3.84 and 3.59 (2 H, AB, 3-H 2, 2 J = 10.4 Hz), 2.19 (s, 3 H, 5-CH 3), 1.74 (d, 1 H, OH, 3 J = 5.1 Hz), 1.31 (s, 3 H, 2-CH_ { 3}), 1.15 (s, 3 H,
2-CH 3)

13 C-NMR ([D_ {6}] - DMSO):

δ (ppm) = 136.0, 135.7, 135.3, 130.0, 131.6, 128.3, 128.2, 128.1, 124.8, 121.6, 120.3, 115.8, 74.8 (C-1), 55.3
(C-3), 47.0 (C-2), 26.9 (C ( C H 3) 2), 21.2 (C ( C H 3) 2) , 10.4 (CH 3 -5)

MS (ES +, 35 V),

m / z (% relative intensity), 352 (11, (M + H) +), 334 (100)

CHN: calculated C 75.09 H 6.30 N, 3.98 found C 75.21 H 6.37 N, 4.18

Example 16 6- (4-Chlorophenyl) -2,3-dihydro-1-methoxy-2,2,5-trimethyl-7-phenyl-1 H -pyrrolizine

6- (4-Chlorophenyl) -2,3-dihydro-1-hydroxy-2,2,5-trimethyl-7-phenyl-1 H -pyrrolizine is dissolved (Example 15, 0.38 g, 1.08 mmol) in 10 ml of MeOH. The clear solution is briefly treated with HCl gas until a pale precipitate is deposited. It is then diluted with 10 ml of MeOH and the solid is removed from the solvent by aspiration. Wash several more times with MeOH and let it air dry.

Yield: 0.30 g (76%), C 23 H 24 ClNO, 365.9 g / mol

Melting point: 179 ° C

IR (KBr):

1 / λ (cm -1) = 2980, 2935, 2878, 1484, 1463, 1380, 1317, 1181, 1087, 819, 766, 750, 696

1 H-NMR (CDCl 3):

δ (ppm) = 7.25-7.11 (m, 7 H, Ph + AA '), 7.07-7.02 (2 H, BB'), 4.20 (s, 1 H, 1-H), 3.82 and 3.55 (2 H, AB, 3-H 2), 3.03 (s, 3 H, OCH 3), 2.20 (s, 3 H, 5-CH 3), 1.31 (s, 3 H, 2-CH 3), 1.21 (s, 3 H, 2-CH 3)

13 C-NMR (CDCl 3):

δ (ppm) = 136.3, 135.1, 132.1, 130.9, 131.5, 129.1, 128.0, 125.2, 122.2, 121.5, 118.8, 83.5 (C-1), 56.8 (OCH 3), 55.9 (C-3) 47.4 (C-2), 27.5, 20.9 (C ( C H 3) ) 2), 10.7 (CH 3 -5)

CHN: calculated C 75.48 H 6.61 N, 3.83 found C 75.05 H 6.55 N 3.80

Example 17 6- (4-Chlorophenyl) -2,3-dihydro-2,2-dimethyl-1-oxo-7-phenyl-1 H -pyrrolizin-5-yl] t-butyl acetate

T-Butyl 6- (4-chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-ylacetate (Example 9a, 15.0 g, 34.4 mmol) and NBS (13.5 g, 75.8 mmol) in 75 ml of CCl4. 5 ml of water are added and the mixture is heated at a temperature of 70 ° C for 2.5 hours. The cooled reaction mixture is dried over Na2SO4, filtered and the solvent is removed on a rotary evaporator. The residue crystallizes at a temperature of 5 ° C from MeOH. The solvent is removed by aspiration and the crystallized is washed with ice cold MeOH.

Yield: 9.0 g (58%). C 27 H 28 ClNO 3; 450.0 g / mol

Melting point: 180ºC

IR (KBr):

1 / λ (cm -1) = 1728 (CO ester), 1686 (CO ketone), 1541, 1365, 1294, 1144, 1095, 1014, 833, 694

1 H-NMR (CDCl 3):

δ (ppm) = 7.40-7.36 (AA ', 2 H), 7.32-7.19 (m, 5 H, Ph), 7.14-7.09 (BB', 2 H ), 4.10 (s, 2 H, CH 2), 3.50 (s, 2 H, CH 2), 1.47 (s, 9 H, OC (C H 3) 3), 1.38 (s, 6 H, 2-CH 3)

13 C-NMR (CDCl 3):

δ (ppm) = 194.3 (CO), 168.3 ( C O), 133.0, 132.8, 132.1, 131.7, 129.7, 128.7, 127.9, 127 , 0, 128.5, 127.5, 124.7, 82.2 (O C (CH 3) 3), 55.4 (CH 2), 49.6 (C-2 ), 32.5 (C-3), 28.0 (OC ( C H 3) 3), 24.9 (C ( C H 3) 2)

CHN: calculated C 72.07 H 6.27 N 3.11 found C 71.29 H 6.27 N 2.97

Example 18 6- (4-Chlorophenyl) -2,3-dihydro-2,2-dimethyl-1-oxo-7-phenyl-1 H -pyrrolizin-5-ylacetic acid

6- (4-Chlorophenyl) -2,3-dihydro-2,2-dimethyl-1-oxo-7-phenyl-1 H -pyrrolizin-5-yl] t-butyl acetate (Example 17, 14, 0 g, 31.1 mmol) to a solution of 15.0 g of KOH in 180 ml of MeOH and the mixture is heated at reflux for 2 hours, allowed to cool and stirred in 600 ml of water. The solution is brought to pH 3 using concentrated HCl and extracted with 100 ml of diethyl ether. The ether extracts are washed with water and dried over sodium sulfate.
The solution is filtered and the volume is reduced in vacuo until crystallization begins. The solid is collected and dried.

Yield: 10.6 g (86%), C 23 H 20 ClNO 3; 393.9 g / mol

Melting point: 234.3 ° C

IR (KBr):

1 / λ (cm -1) = 2968, 2926 (CH), 1743 (Acid CO), 1650 (CO ketone), 1534, 1364, 1330, 1172, 1107, 696

1 H-NMR ([D_ {6}] - DMSO):

δ (ppm) = 7.43-7.38 (AA ', 2 H), 7.30-7.13 (m, 5 H, Ph), 7.13-7.08 (BB ', 2 H), 4.14 (s, 2 H, CH 2), 3.64 (s, 2 H, CH 2), 1.25 (s, 6 H, 2-CH 3)

13 C-NMR ([D_ {6}] - DMSO):

δ (ppm) = 194.1 (CO) 170.5 (CO), 132.9, 132.1, 131.7, 131.65, 129.3, 128.6, 127.9, 126.8 , 128.4, 127.3, 125.6, 122.9, 54.6 (CH2), 48.9 (C-2), 30.6 (CH2), 24.4 ( C ( C H 3) 2)

CHN: calculated C 70.14 H 5.12 N 3.56 found C 70.09 H 5.09 N 3.65

Example 19 6- (4-Chlorophenyl) -2,3-dihydro-2,2,5-trimethyl-1-oxo-7-phenyl-1 H -pyrrolizine

6- (4-Chlorophenyl) -2,3-dihydro-2,2-dimethyl-1-oxo-7-phenyl-1 H -pyrrolizin-5-ylacetic acid (Example 18,
0.60 g, 1.52 mmol) at a temperature of 245 ° C for 15 minutes. The cooled melt is ground and extracted with 10 ml of diethyl ether. The solvent is removed by aspiration and the crystallized is dried.

Yield: 420 mg (79%) C 22 H 20 ClNO, 349.9 g / mol

Melting point: 227 ° C

IR (KBr):

1 / λ (cm -1) = 2966, 2866, 1682 (CO), 1537, 1461, 1399, 1359, 1322, 1125, 1089, 753, 695

1 H-NMR (CDCl 3):

δ (ppm) = 7.41-7.36 (AA ', 2 H), 7.31-7.18 (m, 5 H, Ph), 7.11-7.06 (BB ', 2 H), 4.01 (s, 2 H, CH 2), 2.25 (s, 3 H, CH 3), 1.38 (s, 6 H, 2-CH 3)

13 C-NMR (CDCl 3):

δ (ppm) = 193.8 (CO), 133.4, 132.5, 132.2, 130.9, 131.6, 129.7, 128.6, 127.9, 126.9, 127 , 2, 125.6, 124.9, 55.0
(C-3), 49.5 (C-2), 25.0 (C ( C H 3) 2), 10.5 (C = C-CH 3)

CHN: calculated C 75.53 H 5.76 N 4.00 found C 75.58 H 5.84 N, 4.13

Example 20 a) 2- [6- (4-Chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-yl] -2-ethyl hydroxyacetate

Dissolve ethyl 6 - [(4-chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-yl] -2-oxoacetate (1.0 g, 2, 4 mmol) prepared in accordance with Laufer et al. (J. Med. Chem. 1994, 37, 1894-1897) in 10 ml of THF. Then a solution of 0.03 g of NaBH4 in 3 ml of water is added and the biphase system is stirred at room temperature for one hour. The organic phase is separated, diluted with approximately 80 ml of water and extracted twice with 20 ml of diethyl ether. The ether phase is washed three times with 100 ml of water, dried over Na2SO4 and concentrated but not completely dried on a rotary evaporator. The product 20a crystallizes after the addition of 10 ml of hexane.

Yield: 0.86 g (86%), C 25 H 26 ClNO 3, 423.9 g / mol

Melting point: 117 ° C

IR (KBr):

1 / λ (cm -1) = 3456 (OH), 2956, 2870, 1736, (CO ester), 1603, 1448, 1213, 1065, 1014, 698

1 H-NMR ([D_ {6}] - DMSO):

δ (ppm) = 7.38-7.34 (AA ', 2 H), 7.19-7.00 (m, 5 H, Ph), 6.99-6.95 (BB', 2 H ), 5.93 (d, 1 H, OH, 3 J = 4.2 Hz), 4.96 (d, 1 H, CH, 3 J = 4.4 Hz), 4, 20-4.00 (m, 2 H, OC H 2), 3.84 and 3.67 (2 H, AB, 3-H 2, 2 J = 11.0 Hz) , 2.82 and 2.68 (2 H, AB, 1-H 2, 2 J = 15.4 Hz), 1.24 (s, 3 H, 2-CH 3), 1.17 (s, 3 H, 2-CH 3), 1.16 (t, 3 H, OCH 2 C H 3, 3 J = 7.1 Hz)

13 C-NMR ([D_ {6}] - DMSO):

δ (ppm) = 171.6 ( C O), 135.5, 134.9, 134.3, 130.7, 131.7, 128.1, 128.0, 127.7, 124.6, 122.8, 122.7, 113.6, 64.8 ( C HOH), 60.7 (CH2), 58.8 (CH2), 42.8 (C-2), 39 , 4 (CH 2), 27.4 (CH 3), 27.1 (CH 3), 14.0 (OCH 2 C H 3)

CHN: calculated C 70.83 H 6.18 N 3.30 found C 71.24 H 6.38 N 3.07

b) 2- [6- (4-Chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-yl] -2-hydroxyacetic acid

Potassium hydroxide (0.50 g) is dissolved in 10 ml of 95% ethanol. 6- (4-Chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-yl] -2-ethyl hydroxyacetate (0.40 g, 0.66 is added mmol) and the mixture is stirred at room temperature for 16 hours. The solvent is then removed on a rotary evaporator and the residue is first purified with diethyl ether and washed, and then treated with 100 ml of water. The solution is acidified to pH 4 using 3M hydrochloric acid. The white acid that is deposited is quickly collected in 20 ml of diethyl ether. The organic phase is separated, washed with 20 ml of water, dried over sodium sulfate, filtered and the solvent is evaporated.

Yield: 0.18 g (68%) C 23 H 22 ClNO 3, 397.9 g / mol

IR (KBr):

1 / λ (cm -1) = 3402 (s, width, OH), 2956, 2870 (s, aliphatic + CO OH ), 1718, (s, CO), 1603, 1099, 1059, 1012, 837, 696

1 H-NMR ([D_ {6}] - DMSO):

δ (ppm) = 12.8 (s, width, 1 H, COO H ), 7.37-6.94 (m, 9 H, aromatic substituted + unsubstituted), 4.89 (s, 1 H, C H OH), 3.83, 3.66 (2 H, AB system, CH 2, 2 J = 11.0 Hz), 2.80, 2.68 (2 H, AB system, CH 2, 2 J = 15.5 Hz), 1.22 (s, 3 H, 2-CH 3), 1.17 (s, 3 H, 2 CH 3)

13 C-NMR ([D_ {6}] - DMSO:

δ (ppm) = 173.3 (COOH), 135.6, 134.7, 134.5, 130.6, (C quaternary), 131.7, 128.1, 128.0, 127.7, 124.6 (CH, arom.), 123.3, 122.7, 113.5, (Quaternary C), 64.5 (CHOH), 58.8 (CH2), 42.8 (C-2), 39.4 (CH2), 27.4 (CH 3), 27.3 (CH 3)

MS (ES +):

m / z = 396 (27%; (M + 1) +)

Fragments:

m / z = 378 (16), 350 (100)

Example 21 Ethyl 6- (2-benzofuranyl) -2,3-dihydro-2,2-dimethyl-1-methoxy-7-phenyl-1 H -pyrrolizin-5-yl-2-oxoacetate a) Ethyl 6- (2-benzofuranyl) -1-bromo-2,3-dihydro-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-yl-2-oxoacetate

It is heated to reflux 6- (2-benzofuranyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-yl-2-oxoacetate ethyl, (4.3 g, 10 mmol, Laufer et al. Arch. Pharm. Pharm. Med. Chem. 1997, 330, 307-312) and NBS (2.0 g, 11 mmol) for 2 hours with AIBN (100 mg) in CCl4 ( 100 ml) The succinimide is removed from the cooled mixture, the solvent is removed in vacuo and the residue is recrystallized from diethyl ether.

Yield: 4.5 g (89%), C 27 H 24 BrNO 4, 506.41 g / mol

IR (KBr):

1 / λ (cm -1) = 2985, 2966, 1734 (CO ester), 1603, 1457, 1444, 1376, 1267, 1253, 1182, 1169, 1078, 1066, 1014, 760, 725, 693

1 H-NMR ([D_ {6}] - DMSO):

δ (ppm) = 7.47-7.20 (m, 9H, 2 Ar.), 6.52 (s, 1H, 3-CH furan); 4.97 (s, 1 H, CH); 4.38-4.13 (AB, 2H, CH2), 3.75-3.68 (m, 2H, CH2), 1.51 (s, 3H, CH 3); 1.28 (s, 3H, CH 3), 1.05-0.98 (t, 3H, CH 3)

13 C-NMR ([D_ {6}] - DMSO):

δ (ppm) = 177.4, 163.7, 154.7, 148.8, 143.2, 132.5, 129.1, 128.6, 128.5, 128.4; 128.4; 127.4; 124.6; 124.1; 123.8; 123.1; 121.1: 121.1; 111.0; 107.4; 62.2; 59.1; 54.4, 48.3; 26.4; 24.9; 13.5

b) Ethyl 6- (2-benzofuranyl) -2,3-dihydro-2,2-dimethyl-1-methoxy-7-phenyl-1 H -pyrrolizin-5-yl-2-oxoacetate

Ethyl 6- (2-benzofuranyl) -1-bromo-2,3-dihydro-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-yl-2-oxoacetate is suspended (Example 21a, 1, 52 g, 3 mmol) in absolute MeOH (40 ml) and stir at room temperature for 30-45 minutes until a fine precipitate forms. The precipitate is filtered off and washed with MeOH.

Yield: 1.17 g (86.3%), C 28 H 27 NO 5, 457.53 g / mol

IR (KBr):

1 / λ (cm -1) = 1754 (CO), 1720, 1641, 1458, 1440, 1431, 1425, 1251, 1187, 1179, 1094, 1088, 1063, 756

1 H-NMR ([D_ {6}] - DMSO):

δ (ppm) = 7.57-7.23 (m, 9H, 2 Ar.), 6.73 (s, 1H, CH), 4.38 (s, 1H, CH), 4.15-4.13 (m, 2H, CH2), 3.60-3.55 (s, 2H, CH2), 3.02 (s, 3H, CH3), 1.24 (s, 3H, CH 3), 1.18 (s, 3H, CH 3), 0.94-0.87 (t, 3H, CH 3)

also you get a small amount of

Methyl 6- (2-benzofuranyl) -2,3-dihydro-2,2-dimethyl-1-methoxy-7-phenyl-1 H -pyrrolizin-5-yl-2-oxoacetate

C 27 H 25 NO 5, 443.50 g / mol

1 HNMR (CDCl 3):

δ (ppm) = 7.55-7.10 (m, 9H, 2 Ar.), 6.49 (s, 1H, 3-CH furan), 4.21 (s, 2H, CH2), 4.18 (s, 1H, CH), 3.35 (s, 3H, CH3), 3.06 (s, 3H, CH 3), 1.33 (s, 3H, CH 3), 1.22 (s, 3H, CH 3)

1 HNMR ([D 6] - DMSO): AB system of group 3-CH_ {2}

Example 22 6- (2-Benzofuranyl) -2,3-dihydro-2,2-dimethyl-1-methoxy-7-phenyl-1 H -pyrrolizin-5-yl-2-oxoacetic acid

Ethyl 6- (2-benzofuranyl) -1-bromo-2,3-dihydro-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-yl-2-oxoacetate is suspended (Example 21a, 1, 1 g, 2 mmol) in NaOH in methanol, prepared from Na (0.52 g, 20 mmol) in MeOH (40 ml), and refluxed for 2 hours. After removing the solvent in vacuo, the residue is distributed in water and the neutral compounds are extracted with ethyl acetate and removed. The acidified aqueous phase at pH 3 with HCl (10%) is extracted again with ethyl acetate. The organic phase of the acidic compounds is dried (Na2SO4) and concentrated.

Yield: 0.65 g (77%), C 26 H 23 NO 5, 429.48 g / mol.

IR (KBr):

1 / λ (cm -1) = 3430, 2959, 2939, 1721, (Acid CO), 1621 (sh), 1608, 1458, 1446, 1369, 1272, 1254, 1081, 1072, 1064, 752

1 H-NMR ([D_ {6}] - DMSO):

δ (ppm) = 7.60-7.15 (m, 9H, 2 Ar.), 6.67 (s; H; CH), 4.34 (s, 1H, CH), 4.14-4.11 (AB, 2H, CH2); 3.00 (s, 3H, CH3); 1.24 (s, 3H, CH3); 1.17 (s, 3H, CH3),

in CDL_ {3}: no dissociation of the group methylene in position 3

13 C-NMR (CDCl 3):

δ (ppm) = 179.0; 165.3; 154.0; 148.6; 143.1; 133.1; 128.8; 128.4; 128.3; 127.1; 124.4; 122.9; 122.5; 122.5; 121.4; 121.2; 111.1; 107.2; 82.0; 59.7; 59.7; 57.3; 46.7; 26.1; 20.1

Example 23 6- (2-Benzofuranyl) -2,3-dihydro-2,2-dimethyl-1-methoxy-7-phenyl-1 H -pyrrolizin-5-ylacetic acid

It is heated at a temperature of 60 ° C for 30 minutes 6- (2-benzofuranyl) -2,3-dihydro-2,2-dimethyl-1-methoxy-7-phenyl-1 H -pyrrolizin-5-yl-2-oxoacetate of ethyl (Example 21b, 0.92 g, 2 mmol) in diethylene glycol (20 ml) with 80% hydrazine hydrate (1.56 ml, 40 mmol), and then treated with 85% KOH (2.1 g, 32 mmol) and the mixture is maintained at a temperature of 130 ° C for 4 hours (until the end of the gas emission and fading of the coloration). The mixture is then poured onto ice, brought to pH 3 with 10% HCl and the fine precipitate is collected by aspiration and dried over P 2 O 5.

For purification, the crude acid (1.0 g) is adsorbed on neutral Al 2 O 3, impurities are removed by elution with diethyl ether, and then desorbed using a saturated NaH2PO4 solution and collected in ether. He Filtered ether extract is concentrated to dryness.

Yield: 0.45 g, C 26 H 25 NO 4, 415.49 g / mol

1 H-NMR ([D_ {6}] - DMSO):

δ (ppm) = 12.6 (width, 1H, COOH), 7.60-7.15 (m, 9H, 2 Ar.), 6.46 (s; 1H, 3-CH furan), 4.23 (s, 1H, 1-CH), 3.90-3.65 (2 AB, 4H, 2 CH2), 2.95 (s, 3H, OCH 3); 1.24 (s, 3H, CH 3); 1.13 (s, 3H, CH 3)

13 C-NMR (CDCl 3):

δ (ppm) = 181.3; 163.6; 162.6; 145.4; 143.7; 138.7; 138.5; 138.1; 135.9, 133.2; 132.55; 132.43; 130.3; 128.3; 122.3; 120.5; 112.3; 92.6; 66.2; 65.7; 57.1; 41.2; 36.6; 30.45

Example 24 2- [6- (2-Benzofuranyl) -2,3-dihydro-2,2-dimethyl-1-methoxy-7-phenyl-1 H -pyrrolizin-5-yl] -2-hydroxyacetic acid

It is obtained from 2- [6- (2-benzofuranyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1 H -pyrrolizin-5-yl] -2-ethyl oxoacetate (S. Laufer et al. Arch. Pharm. Pharm Med. Chem. 1997, 330, 307-312) following the method described in Example 20.

Yield: 0.28 g (65%) crystallized with diethyl ether C 27 H 27 NO 4, 429.52

IR (KBr):

1 / λ (cm -1) = 3431, 2958, 1730 (CO ester), 1603, 1454, 1369, 1254, 1164, 1065, 1024, 751, 700

1 H-NMR (CDCl 3):

δ (ppm) = 7.55-7.10 (m, 9H, 2 Ar.); 6.50 (d; 1H, 3-CH furan, J = 0.6 Hz), 5.53 (d, 1H, C H OH, J = 2.0 Hz), 4.35-4.1 (ABX_ 3, 2H, OC H 2 CH 3); 3.88 / 3.62 (AB, 2H, J_B = 10.6 Hz, CH2), 3.39 (d, OH; J = 2.0 Hz), 2.80 / 2, 67 (AB, 2H, CH2, J_B = 15 Hz); 1.35-1.15 (2 s + t, 9H, C (CH 3) 2, OCH 2 C H 3)

13 C-NMR (CDCl 3):

δ (ppm) = 172.9; 154.4; 152.1, 135.9, 135.4, 129.2, 128.2, 128.1, 125.4, 123.3, 122.4, 120.3, 115.7, 114.7, 111.0, 104.1, 65.7, 62.5, 58.9, 53.5, 39.8, 27.9, 27.6, 14.1

Example 25 2- (4-Chlorophenyl) -6,6-dimethyl-1-phenyl-6,7-dihydro-5 H -pyrrolizin-3-yl ester of benzoic acid

A solution of 6- (4-chlorophenyl -) - 2,2-dimethyl-7-phenyl-2,3-dihydro-1 H -pyrrolizine (1.6 g, 5 mmol, prepared in accordance with Laufer et al. J Med. Chem. 1994, 37, 1894-7) in anhydrous diethyl ether (100 ml) is cooled to a temperature of -70 ° C under an argon atmosphere and added dropwise and stirring a solution of tert-butyllithium (3.13 ml, 1 molar / 15%, 5 mmol) in n-pentane at this temperature so that the initially red color changes back to yellow. After stirring at a temperature of -70 ° C for an additional 2 hours, the solution is allowed to warm to room temperature and stirring continues for another 1 hour to complete the formation of anions, and is cooled again to -70 ° C. To the solution of 2- (4-chlorophenyl) -6,6-dimethyl-1-phenyl-6,7-dihydro-5 H -pyrrolizine with lithium in position 3 thus prepared is added, dropwise, a dehydrated solution of dibenzoyl peroxide (1.93 g, 75-80%, moistened with H2O, 6 mmol) in diethyl ether (50 ml) using CaCl2 and a 3 Amstrong molecular sieve. The mixture is allowed to warm to room temperature and stirred until the initial compound has completely disappeared (16-20 hours). The solution is treated with water and the aqueous phase is extracted twice (100 ml) with diethyl ether. The ether phase is dried over drying Na2SO4 and the solvent is completely removed at low pressure after filtration of the drying agent. The residue recrystallizes from n-hexane in the presence of heat. 1.16 g (53% of theory) of a crystallized with a melting point of 193 ° C.

Yield: 53%, 1.16 g, C 28 H 24 ClNO 2, Molec Mass. = 441.96

Calculated: C 76.10% H 5.47% Cl 8.02% N 3.17% Or 7.24%

IR (NaCl):

1 / λ (cm -1) = 2956, 1745; 1601; 1542; 1450; 1258; 1176; 1054; 1014; 768; 699

1 H-NMR (CDCl 3):

δ (ppm) = 8.15-8.11 (m, 2H, arom.); 7.70-7.40 (m, 3H, arom.); 7.25-7.10 (m, 9H, arom.); 3.66 (s, 2H, CH2); 2.86 (s, 2H, CH2), 1.29 (s, 6H, C (CH 3) 2)

13 C-NMR (CDCl 3):

δ (ppm) = 165.0; 135.8; 134.1; 132.7; 131.2; 130.5; 130.4; 129.6; 129.1; 128.7; 128.4; 128.2; 128.1; 125.0; 113.4; 110.8; 77.2; 58.1; 43.5; 40.3; 27.8

MS (ES +, 35 V):

m / z = 442/444 ((M + H) +, 100%)

Example 26 [2- (4-Chlorophenyl) -6,6-dimethyl-1-phenyl-6,7-dihydro-5 H -pyrrolizin-3-yl] 2- (4-chlorophenyl) -6,6-dimethyl- acetate 1-phenyl-6,7-dihydro-5 H -pyrrolizin-3-yl

A solution of [2- (4-chlorophenyl) -6,6-dimethyl-1-phenyl-6,7-dihydro-5 H -pyrrolizin-3-yl] acetic acid (38.0 g, 0.1 mol) in anhydrous diethyl ether (400 ml), it is treated at room temperature with BF3 etherate (2 ml, 2.26 g, 0.016 mol) and stirred for 30 minutes. The solution (200 ml), which at that time is violet, is then concentrated at low pressure and is completed with n-heptane (200 ml). The residual ether (150 ml) is removed at low pressure and the violet crystallized residue is separated from the ether-heptane mother liquor. The mother liquors are concentrated to dryness (5.5 g) and the concentrate is taken up in ethanol (50 ml) in the presence of heat. After cooling (16 hours), the blue solution is removed by aspiration from the insoluble residue. The crystallized is washed with iced ethanol and, if necessary, recrystallized again from a little ethanol (10 ml). 0.45 g of the desired compound are obtained. The substance can also be purified by column chromatography (SiO2, hexane / ether 9: 1) (rf 0.2, rf of ethyl ester 0.22).

Yield: 1.3%, 0.45 g, C_ {44} H_ {40} Cl_ {N} {2} O2, Molec Mass. = 699.73

calculated: C 75.53% H 5.76% Cl 10.13% N 4.00% OR 4.57% found: C 75.14% H 5.75% N 4.07%

IR (NaCl):

1 / λ (cm -1) = 2960; 2872; 1768; 1601; 1541; 1536; 1451; 1112; 1094; 833; 698

1 H-NMR (CDCl 3):

δ (ppm) = 7.25-7.01 (m, 18, arom.); 3.71 (s, 2H, CH2); 3.52 (s, 2H, CH2), 3.41 (s, 2H, CH2), 2.81 (s, 2H, CH2), 2.78 (s, 2H, CH2), 1.27 (s, 6H, C (CH 3) 2), 1.15 (s, 6H, C (CH 3) 2)

13 C-NMR (CDCl 3):

δ (ppm) = 27.80; 31.06; 40.17; 40.37; 43.06; 43.51; 57.81; 58.21; 110.66; 113.33; 115.06; 115.91; 124.14; 124.77; 125.07; 128.09; 128.12; 128.13; 128.24; 128.35; 128.44; 129.04; 129.36; 130.41; 131.19; 131.56; 131.84; 132.47; 134.58; 134.66; 135.50; 135.74; 169.13

MS (70 eV, PI-FDMS, + VE, + HMR, B scan):

m / z = 698.2 (M +, 100%), 699.2 (M +, 50%), 700.2 (M +, 75%), 701.2 ( M +, 35%), 702.3 (M +, 18%)

MS (ES +, 35 V):

m / z (% relative intensity) (M + H) +: 699 (32), 700 (18), 701 (20), 702 (10), 703 (7); 334 (65), 335 (15), 336 (100), 337 (25), 338 (80), 339 (18), 340 (19)

MS (EI, 70 eV):

m / z (% of relative intensity) (M +): 698 (1), 699 (0.7), 700 (1), 334 (100), 335 (42), 336 (60), 337 (58), 338 (18), 339 (15)

Example 27 2- (4-chlorophenyl) -7a-hydroxy-6,6-dimethyl-1-phenyl-5,6,7,7a-tetrahydro pyrrolizin-3-one

The 2- (4-chlorophenyl) -6,6-dimethyl-1-phenyl-6,7-dihydro-5 H -pyrrolizin-3-benzoate (0.4 g, 0.9 mmol) described in Example 25 is suspended in MeOH (20 ml) and treated with a solution of NaOH (1 ml, 10%) and then heated at reflux for 3 hours until the disappearance of the educt (tlc: SiO2 / diisopropyl ether, rf 0 , 95), then the alcohol is removed in vacuo. The aqueous residue is treated with water (20 ml) and with diethyl ether (30 ml) and acidified (pH = 2-3) with HCl (10%). The ether phase is separated, the aqueous phase is extracted 3 times with ether (100 ml) and the collected ether phases are combined, dried over drying Na2SO4 and the solvent is concentrated under low pressure. As a residue, 0.39 g of a solid mixture of substances remains, which is purified by column chromatography (SiO2 / diisopropyl ether, rf 0.55). Fractions 8-13 (10 ml each) contain 120 mg (40%) of the title compound.

Yield: 40%, 120 mg, C_ {21} H_ {20} ClNO_ {2} Molec mass. = 353.85

Calculated: C 71.28% H 5.70% Cl 10.02% N 3.96% Or 9.04%

IR (NaCl):

1 / λ (cm -1) = 3355; 1680; 1394; 1092; 1068; 696; 530

1 H-NMR (DMSO-d6):

δ (ppm) = 7.45-7.23 (m, 9H, arom.); 3.60 / 3.22 (AB, CH2, J_B = 11.5 Hz); 2,195 / 1,962 (AB, CH2, J_B = 11.5 Hz); 1,367 (s, 3H, CH 3); 1,067 (s, 3H, CH 3)

MS (ES +, 35 V):

m / z (% relative intensity) MH +: 354 (100), 355 (20), 356 (35), 357 (7); (MH-H2O) +: 336 (40), 337 (5), 338 (10), 339 (2)

In no case was it possible to detect 2- (4-chlorophenyl) -6,6-dimethyl-1-phenyl-5,6,7,7a-tetrahydropyrrolizin-3-one (2- (4-chlorophenyl ketone tautomer) - 6,6-dimethyl-1-phenyl-6,7-dihydro-5 H -pyrrolizin-3-ol) was expected as a saponification product.

After relatively long rest (16 hours) of a solution in CHCl3 of the product, the 2- (4-chlorophenyl) -6,6-dimethyl-1-phenyl-5,6-dihydropyrrolizin-3-one described in Example 29 in the form of a pure substance (elimination of H2O).

Example 28 2- (4-chlorophenyl) -6,6-dimethyl-1-phenyl-6,7-dihydropyrrolizin-3-one

(Acetoxylation method according to L. Eberson and L. Jönson, Acta chem. Scand. Ser. B 30, 361 (1976))

It is suspended in anhydrous acetic acid (20 ml) and stirred at a temperature of 100 ° C for 4 hours 6- (4-chlorophenyl) -2,2-dimethyl-7-phenyl-2,3-dihydro-1 H -pyrrolizine ( 1.6 g, 5 mmol, see above), dipotassium peroxodisulfate (1.62 g, 6 mmol), palladium (II) acetate (0.05 g, 0.2 mmol) and 2,2'-bipyridyl ( 0.02 g, 0.1 mmol) and 2,2'-bipyridyl (0.02 g, 0.1 mmol) (note: in advance, no reaction was observed at room temperature after 4 hours).

The dark solution of glacial acetic acid is neutralize with a solution of Na2CO3 (pH 7) and extract three times with ether (150 ml). The ether solution is washed with a NaHCO3 solution, dried on drying Na2SO4 and the Solvent is removed at low pressure. The residue is purified by short column of SiO2 using n-hexane / diisopropyl ether as eluent.

Yield: 88%, 1.48 g, C 21 H 18 ClNO, Molec. Mass = 335.84

Calculated: C 75.11% H 5.40% Cl 10.56% N 4.17% Or 4.76%

IR (NaCl):

1 / λ (cm -1) = 2956; 1689; 1483; 1379; 1093; 833; 739; 696

1 H-NMR (CDCl 3):

δ (ppm) = 7.43-7.24 (m, 9H, arom.); 5.61 (s, 1 H, CH); 3.68 (s, 2H, CH2); 1.35 (s, 6H, C (CH 3) 2)

MS (ES +, 35V):

m / z (% relative intensity) MH +: 336 (100), 337 (15), 338 (37), 339 (7)

The same substance is formed by letting the substance of Example 28 (see above) in solution (for example, in CHCl3).

Claims (10)

1. Pyrrolizine compounds of Formula I 14 in the which

\ circ

R1 and R2 can be identical or different, being aryl groups or aromatic groups mono or bicyclic, heterocyclic with 1, 2 or 3 heteroatoms that, independently, they are selected from N, O and S, where R1 and R2 groups may optionally be substituted by 1, 2 or 3 groups, which, independently of each other, are selected from alkyl, halogen, CF3, hydroxy, alkoxy, aryloxy and CN, and optionally they can be condensed with phenyl or naphthyl;

\ circ

R3 is H, a alkyl group, COOH, COOalkyl, COOAlkPh, COCOOalkyl, CHO or A-Y, where

TO

is a group alkylene of 1 to 8 carbon atoms or alkenylene of 2 to 8 atoms carbon, optionally substituted with hydroxyl or alkoxy,

AND

is COOH, SO3H, OPO (OH) 2, OP (OH) 2, tetrazolyl, COOalkyl, SO3 alkyl, CHO or OH;

Alk

is a group alkylene of 1 to 4 carbons;

\ circ

R4, R5, R6 and R7, identical or different, are H, alkyl, hydroxyalkyl or alkoxyalkyl;

\ circ

one of the R8 and R9 groups is H, alkyl, hydroxyalkyl or alkoxyalkyl, and the another is hydroxyl, alkoxy, carboxyl or acyloxy or R8 and R9, together with the carbon atom to which they are attached, they form a group carbonyl,

as well as its optical isomers, its salts physiologically tolerable and its easily hydrolysable esters physiologically 2. Compounds of Formula I according to claim 1, wherein R3 is H, an alkyl group, COOH, CHO or
AY, where A is an alkylene group of 1 to 8 carbon atoms, optionally substituted with OH, and Y is COOH, SO 3 H, OPO (OH) 2, CHO or tetrazolyl. 3. Compounds of Formula I according to claim 1 or 2, wherein R3 is H, an alkyl group, COOH, CHO or
AY, where A is an alkylene of 1 to 8 carbon atoms, optionally substituted with OH, and Y is COOH. 4. Compounds of Formula I according to any of the preceding claims, wherein R1 and R2, identical or different, they are aryl groups, or an aromatic group 5 or 6-membered heterocyclic wherein R1 and R2, independently with each other, they can have 1 or 2 halogen, hydroxy substituents, alkoxy and / or CF 3, and where the heterocyclic radical may be condensed with a phenyl group. 5. Compounds of Formula I according to claim 4, wherein R1 and R2, identical or different, are phenyl, phenyl substituted with 1 or 2 halogen atoms or groups hydroxyl, thienyl or benzofuranyl. 6. Compounds of Formula I according to claim 4, wherein R1 is phenyl and R2 is a phenyl group or benzofuranyl monohalo- or monohydroxy substituted. 7. Compounds of Formula I according to any of the preceding claims, wherein R4 is hydroxyalkyl, R5 is H or alkyl and R6 and R7, independently of each other, are H or I rent. 8. Compounds of Formula I according to any of the preceding claims, wherein R8 and R9, together with the atom of carbon to which they are attached, are a carbonyl group. 9. Pharmaceutical composition comprising less a compound according to any of claims 1 to 8, if it is the case together with vehicles and / or pharmaceutical additives acceptable. 10. Use of at least one compound according to any of claims 1 to 8 for the preparation of a pharmaceutical composition for the prevention of disorders induced allergies or for the treatment of type disorders rheumatic.