DE19845446A1 - New hydroxy, alkoxy, acyloxy and oxo substituted pyrrolizine derivatives useful for treatment of rheumatic and allergic disorders, e.g. psoriasis, urticaria and eczema - Google Patents

Abstract

1-(Hydroxy, alkoxy, acyloxy or oxo)-6,7-di(hetero)aryl-pyrrolizine derivatives are new. Pyrrolizine derivatives of formula (I) and their optical isomers, salts and physiologically hydrolysable esters are new: R<1>, R<2> = aryl or mono- or bicyclic heteroaryl containing 1-3 N, O and/or S atoms (each optionally substituted by 1-3 alkyl, halo, CF3, alkoxy, aryloxy and/or CN and optionally fused with phenyl or naphthyl); R<3> = H; alkyl; COOH; COO-alkyl; COO-Alk-phenyl; COCOOH; COCOO-alkyl; CHO; or A-Y; A = 1-8C alkylene or 2-8C alkenylene optionally substituted by OH or alkoxy; Y = COOH; SO3H; OPO(OH)2; OP(OH)2; tetrazolyl; COO-alkyl; SO3-alkyl; CHO; or OH; Alk = 1-4C alkylene; R<4>-R<7> = H or alkyl; one of R<8> and R<9> = H or alkyl; and the other is OH; alkoxy; or acyloxy; or R<8> + R<9> = oxo.

Description

The present invention relates to anti-inflammatory oxo and Hydroxy derivatives of pyrrolizines, pharmaceutical agents which contain these compounds and their use in pharmacy.

Pharmacologically active pyrrolizine compounds which Lipoxygenase (5-LO) and Cyclooxygenase 1 and 2 (Cox-1 and Cox- 2) inhibit are already known. For example, anti logistically effective pyrrolizine compounds described 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. The most promising connection this type is the 6- (4-chlorophenyl) -7-phenyl-2,3-dihydropyrrolo- [1,2-a] pyrrole compound ML 3000, see. Drugs of the Future, 1995, 20th (10): 1007-1009. It suppresses the release of leukotrienes, Thromboxanes and prostaglandins. The inhibitory effect on the formation of the leukotrienes and prostaglandins is with this Structure balanced, harmful effects of a pure inhibitory effect on cyclooxygenase 1 and 2 (Cox-1 and Cox-2) with increased bil The formation of leukotrienes is not observed here. All of them The 1-position of the pyrrolizine structure is unsub stitches.

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

All compounds have a fused diarylpyrrole structural element and a third acidic residue R3 together. Draw the connections characterized by high lipophilicity, good bioavailability and medium Half-lives off.

According to the general disclosure in WO 95/32970 and WO 95/32971 X can represent a carbonyl group. Are connections of this type however according to the in the above-mentioned WO publications and in the The method described in US Pat. No. 5,260,451 cannot be produced.

US 3,705,905 discloses compounds of the formula

where X is methylene, α- or β-hydroxyethylene or carbonyl and R represents a hydroxymethyl group or a formyl group. These compounds have anti-virus, anti-tumor or immunosup pressive activity.

Other pyrrolizine compounds used to treat thrombotic Diseases are useful in US 4,546,100 and US 4,684,658 disclosed.

The object of the present invention was to provide connections to provide, which in comparison to the state of the art as well balanced effect at a high level on the two key Enzyme systems of the arachidonic acid cascade, namely 5-lipoxygenase and exercise the cyclooxygenases.

Surprisingly, it has now been found that this task is accomplished by Pyrrolizine compounds is dissolved, which is a sow in the 1 position  erstofffunktion, such as a carbonyl group, a hydroxy group or have an alkoxy group.

The present invention therefore relates to pyrrolizine compounds of the formula I.

wherein
R1 and R2, which may be the same or different, represent aryl or an aromatic mono- or bicyclic, heterocyclic radical which has 1, 2 or 3 heteroatoms which are independently selected from N, O and S. where the radicals R1 and R2 are optionally substituted by 1, 2 or 3 groups which are selected independently of one another from alkyl, halogen CF ₃ , alkoxy, aryloxy and CN, and can optionally be fused with phenyl or naphthyl;
R3 represents H, alkyl, COOH, COOalkyl, COOAlkPh, COCOOalkyl, CHO or AY, where
A represents C ₁ -C ₈ alkylene or C ₂ -C ₈ alkenylene, which may optionally be substituted by hydroxyl or alkoxy,
Y is COOH, SO ₃ H, OPO (OH) ₂ , OP (OH) ₂ , tetrazolyl, COOalkyl, SO ₃ alkyl, CHO or OH;
Alk represents C ₁ -C ₄ alkylene;
R4, R5, R6 and R7, which may be the same or different, are H or alkyl;
one of the radicals R8 and R9 represents H or alkyl and the other represents hydroxyl, alkoxy or acyloxy or R8 and R9 together with the carbon atom to which they are attached represent a carbonyl group,
and the optical isomers, physiologically acceptable salts and physiologically readily hydrolyzable esters thereof.

The physiologically tolerated salts can in the present case Acid addition or base addition salts. For acid additions salts use inorganic acids such as hydrochloric acid, sulfur acid or phosphoric acid, or organic acids, such as tartaric acid, Lactic acid, citric acid, malic acid, mandelic acid ascorbic acid, Maleic acid, fumaric acid, gluconic acid and the like.

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

Physiologically easily hydrolyzable esters of the compounds of the Formula I are, for example, alkyl, pivaloyloxymethyl, acetoxyme thyl, phthalidyl, indanyl and methoxymethyl esters.

Insofar as the compounds according to the invention have centers of asymmetry sen, are racemates and optical isomers (enantiomers, diastereo mere).

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

Unless otherwise stated, "alkyl" preferably represents C ₁ -C ₈ alkyl, in particular C ₁ -C ₆ alkyl and particularly preferably C ₁ -C ₄ alkyl.

"Aryl" preferably represents naphthyl and especially phenyl.

The term "halogen" includes fluorine, chlorine, bromine or iodine atom and in particular a fluorine or chlorine atom.

"Alkylene" or "alkenylene" stands for straight-chain or branched Alkylene or alkenylene groups with preferably 1 to 6 or 2 to 6 and in particular 1 to 4 or 2 to 4 carbon atoms. The Al kylene group and especially the methylene group is preferred.

"Acyl" stands for RCO, with R preferably. the above for "alkyl" and "Aryl" has the meanings given. Acetyl is especially imminent moves.

The "aromatic heterocyclic radical" is in particular a 5- and 6-membered heterocyclic radical which can be substituted and condensed as indicated above. Examples are a thiophene, pyrrole, imidazole, thiazole, thiadiazole, fu ran, oxazole, isoxazole, pyridine, pyrimidine, benzofuran or quinoline residue. If the heterocycle is substituted, there are 1, 2 or 3 substituents which are selected from halogen, CF ₃ , C ₁ -C ₈ alkyl and C ₁ -C ₈ alkoxy. Preference is given to a thiophene or halogen, in particular chlorine-substituted, thiophene residue, a furan, pyridine, benzofuran or quinoline residue.

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

R1 and R2 are particularly preferably phenyl, halogen substituent ized phenyl (substituted with 1 or 2 halogen atoms, especially chlorine atoms), thienyl or benzofuranyl. Particularly preferred R1 is phenyl and R2 is phenyl, that with 1 or 2 halo  toms, especially chlorine atoms, is substituted.

Compounds of the formula I in which R3 is COOalkyl, COOAIkPhenyl, CO COOalkyl or AY, where A and Alk have the meanings given above and Y is COOalkyl, SO ₃ alkyl or OH, are intermediate products which are used for the preparation of the pharmacologically active compounds of formula I are useful. Pharmacologically active compounds of the formula I are therefore those in which R3 is H, alkyl, COOH, CHO or AY, where A has the meanings indicated above and Y is COOH, SO ₃ H, OPO (OH) ₂ , PO (OH) ₂ , CHO or tetrazolyl.

R3 is preferably H, alkyl, COOH, CHO or AY, where A is C ₁ -C ₈ -alkylene which is optionally substituted by OH and Y is COOH.

The radicals R6 and R7 are preferably H and the radicals R4 and R5 preferably for alkyl, especially methyl.

A preferred embodiment are compounds of the formula I in which R1 is phenyl, R2 is phenyl which is substituted by 1 or 2 halogen atoms, in particular chlorine atoms; R3 represents H, COOH, CHO, CH ₂ COOH or CH (OH) COOH; and R4 to R9 have the meanings given above.

The compounds according to the invention are prepared by Oxidation in 1 position. Ver serves as the starting compounds Compounds of formula II, see the following synthesis scheme 1. The compounds of formula II are prepared in accordance with above-mentioned prior art and in particular according to the in US 5,260,451 and WO 95/32970, WO 95/32971 and WO 95/32972 procedure.

For the preparation of compounds of the formula I in which R3 is COOH, COOAlkyl, COOAlkPhenyl, COCOOAlkyl or CHO, the Ver  Compounds of formula II in a known manner with N-bromosuccinimide (NBS) in the presence of a radical initiator, such as azo-bis-isobutyro nitrile in a chlorinated solvent such as carbon tetrachloride fabric, implemented. The reaction temperature is chosen so that the radical reaction takes place, for example at 70 to 90 ° C.

When using 1 molar equivalent of N-bromosuccinimide, the Compound of the formula III brominated in the 1-position. This in turn can then with acylates, for example sodium acetate or alcohol ten, such as sodium methylate or sodium ethylate, to the corresponding Compounds of formula Ic and Id are implemented. The implementations are carried out in a known manner, the reaction with the Acy laten is carried out in an inert solvent, for example dime thylformamide (DMF), at 70 to 90 ° C. The implementation of the connection gene of formula III with alcoholates is conveniently carried out in the appropriate alcohol. Alternatively, the connections of For mel III, without being isolated from the reaction mixture, directly implemented with an alcohol to the compounds of formula Ib the.

Alternatively, you can a compound of formula II with a Molä equivalent of NBS in a chlorinated solvent in the presence of Convert water to a compound of formula Ia. With a wide one Ren molar equivalent of NBS then gives a compound of the formula Ib.

In the synthesis schemes, acyl has the meanings given above. R represents an alkyl radical.  

Synthesis scheme 1

Compounds of the formula I according to the invention, in which R3 stands for a hydrogen atom, are preferably attacked by oxidizing agents on the pyrrole nucleus, see Arch. Pharm. 318, 661-663 (1985); 663-664 (1985); 319, 231-234 (1986) and 312, 896-907 (1985). Compounds of the formula I in which R3 is an aliphatic radical (for example CH ₂ COOH, CH ₃ ) are preferably attacked on these aliphatic substituents. To prepare compounds of the formula I in which R3 represents a hydrogen atom, the reactive 5-position is therefore initially blocked. As shown in synthesis scheme 2, this takes place starting from compounds of formula V, the preparation of which is also described in the abovementioned prior art and in particular in US Pat. No. 5,269,451 and WO 95/32970, WO 95/32971 and WO 95/32972, by introducing an acyl function. For this purpose, a compound of formula V is reacted with chloroformic acid trichloromethyl ester in an inert solvent, for example tetrahydrofuran or dioxane, and the intermediate ester is reacted with methanol to give a compound of formula VI. This is then implemented analogously to synthesis scheme 1 with 2 molar equivalents of N-bromosuccinimide in carbon tetrachloride and in the presence of water to give a compound of the formula Ie. By basic ester cleavage in a conventional manner, for example with potassium hydroxide in methanol or water, the carboxylic acid of the formula Is is obtained. This in turn can be decarboxylated at 250 to 350 ° C. to a compound of the formula Ig (R3 = H). The compounds of the formula Ig can then be functionalized at position 5 using conventional methods, for example by Vilsmeyer-Formylierurlg with phosphorus oxychloride in dimethylformamide (DMF) to give a compound of the formula Is fetch function can be reduced, for example with complex hydrides such as lithium aluminum hydride. The alcohol function in the 5-position can then be etherified or esterified in a customary manner, giving compounds of the formula Ic and Id (R3 = H).

Alternatively, the compound of formula VI with a mole equiva lent N-bromosuccinimide and then with an alcoholate into one Compound of formula Ii are implemented. By ester splitting and Decarboxylation in the manner given above gives Ver bonds of formula Ij and Ik.  

Synthesis scheme 2

An alternative to introducing an acyl function into a verb Formation of formula V consists in the way shown in synthesis scheme 3. Here, a compound of formula V with ethyl oxalate chloride in an inert solvent such as THF or dioxane ner compound of formula XV implemented. This in turn will be like already described in connection with synthesis scheme 2, with 2 Molar equivalents of N-bromosuccinimide to a compound of formula II  oxidized, which after hydrolysis (basic ester cleavage as above wrote) gives a compound of formula Im. Alternatively, you can a compound of formula XV with one molar equivalent of N-bromosuccin imide and then with an alcoholate to a compound of Formula to be implemented in the usual way to the free Acid Io can be hydrolyzed. The connection of the formula Io can be further derivatized by reducing the α-keto group of the substituent in the 5-position by Huang Minlon reduction Hydrazine and base. This gives a compound of the formula Ip. A reduction of a compound of the formula Io with a complex one Hydride, for example sodium borohydride in water or an aq alcohol, the compound gives Iq.

Synthesis scheme 3

The oxidative attack of N-bromosuccinimide already mentioned above to aliphatic substituents in the 5-position of the invention Connections can be made more space-filling by introducing them Prevent protection groups in the area of this position. The synthesis takes place starting from compounds of formula IV, the Her position also in the above-mentioned prior art and esp in particular in US 5,260,451 and WO 95/32970, WO 95/32971 and WO 95/32972 is described, according to those described in synthesis scheme 4 procedure. A compound of formula IV with a strongly branched alcohol, such as t-butanol or neopentyl alcohol Presence of an activating agent, for example carbonyldii midazole, in an inert solvent such as tetrahydrofuran or Dioxane, esterified to a compound of formula XXI. Ester XXI is, as described in connection with synthesis scheme 2, with 2 molar equivalents of N-bromosuccinimide in one. Compound of the formula Ir transferred a verb after ester cleavage and decarboxylation of the formula Is or It results. Alternatively, the ester XXI with one molar equivalent of N-bromosuccinimide and then with Alko be converted into a compound of formula Iu. Esterhy Drolysis and decarboxylation then gives a compound of the formula Iv and Iw.  

Synthesis scheme 4

The compounds according to the invention show hem in vitro and in vivo release of various mediators of arachidonic acid cascade, especially 5-lipoxygenase and cyclooxygenases 1 and 2 and therefore a pronounced anti-inflammatory activity. They are therefore suitable for the treatment of diseases in which increased release rates of the eicosanoid mediators for the muck hung or responsible for the progression of these diseases are. In particular, the compounds of the invention are for Treatment of diseases of the rheumatic type and for Prevention of allergy-induced diseases can be used. The Compounds according to the invention are therefore effective anti-inflammatories  stika, analgesic, antipyretic, antiallergic and broncholytic and therefore for the prophylaxis of anaphylactic and septic Shocks as well as for the treatment of dermatological diseases, such as Psoriasis, urticaria, acute and chronic allergic rashes and non-allergic genesis.

The compounds of the invention have increased chemical Sta bilinity, parenteral applicability, improved enteral bioavailability availability and shorter half-lives.

The compounds of the invention can be used either individually therapeutic agents or as mixtures with other therapeu active ingredients are administered. As such, you can ver be submitted, but generally they are in the form of pharma medicinal agent administered, d. H. as mixtures of the active ingredients with suitable pharmaceutical carriers or diluents. The compounds or agents can be administered orally or parenterally be enough, but preferably they are in oral dosage given shape.

The type of pharmaceutical agent and pharmaceutical carrier gers or diluent depends on the desired administration type of consultation. Oral agents can be taken, for example, as tablets or Capsules are present and can contain conventional excipients, such as Binder (e.g. syrup, acacia, gelatin, sorbitol, tragacanth or Polyvinyl pyrrolidone), fillers (e.g. lactose, sugar, corn starch ke, calcium phosphate, sorbitol or glycine), lubricants (e.g. magne sium stearate, talc, polyethylene glycol or silicon dioxide), disine tegrating agents (e.g. starch) or wetting agents (e.g. sodium lauryl sulfate). Oral liquid preparations can be in the form of watery or oily suspensions, solutions, emulsions, syrups, elixirs or sprays etc. are available or can be reconstituted as dry powder stitution with water or another suitable vehicle Such liquid preparations can be conventional additives for example suspending agents, flavors, diluents  or emulsifiers. Can be used for parenteral administration solutions or suspensions with usual pharmaceutical carriers like to use.

The compounds or agents according to the invention can be sucked on animal (human and animal) in doses of about 0.5 mg to about 100 mg each kg body weight per day. You can in one Single dose or in multiple doses.

The spectrum of activity of the compounds was determined using the following test systems examined:

Test system for determining the inhibition of 5-lipoxygenase

Human granulocytes serve as the source of the 5-lipoxygenase. By stimulation with calcium ionophore A 23187 LTB ₄ (leukotriene B ₄ ) is formed from endogenous arachidonic acid. The granulocytes are isolated and the enzyme reaction is carried out by known methods (see Arch. Pharm. Med. Chem. 330, 307-312 (1997)).

The blood, which is protected against coagulation with heparin, is centrifuged over a continuous Percoll® gradient and the granulocyte layer is pipetted off. After lysis of the erythrocytes, the granulocytes are washed several times and then adjusted to a certain number of cells. The enzyme reaction is then started with calcium ionophore A 23187 in the presence or absence of the test substance after addition of Ca ²⁺ . The synthesis of the leukotrienes is stopped after 1.5 minutes. The samples are centrifuged off and the supernatant diluted. LTB ₄ is determined quantitatively by means of ELISA.

Test system for determining the inhibition of cyclooxygenase-1

In this test system, the amount of prostaglandin E ₂ formed by human platelets after the addition of calcium ionophore is determined using an ELISA. The platelets are obtained after centrifugation via a discontinuous Percoll® gradient. The enzyme reaction and the determination of the metabolites formed are basically the same as for the determination of 5-lipoxygenase inhibition. There are differences in the incubation period. Furthermore, the addition of a thromboxane synthase inhibitor is necessary (see Arch. Pharm. Med. Chem. 330, 307-312 (1997)).

Test system for determining the inhibition of cyclooxygenase-2

COX ₂ (from placenta of the sheep) is pre-incubated with test substance for 10 min at 4 ° C, then stimulated with arachidonic acid (5 µM) at 25 ° C for 10 min. Diclofenac (IC ₅₀ (COX ₂ ) = 3.0 10 ^-6 M) serves as a reference. The determination is carried out in 3 dilutions (10 ^-7 , 10 ^-6 , 10 ^-5 M). The PGE ₂ concentrations are quantified by means of ELISA (see Mitchell, JA et al. Proc. Nat. Acad. Sci 90: 11693-11697 (1993)).

Determination of the distribution coefficient

The distribution coefficient P of the connections was determined in the system n- Octanol / water according to the OECD Guidline for Testing Chemicals, no. 117, definitely.

The results are summarized in Table 1 below poses.  

Table 1

IC ₅₀ (in µmol) and Log P values

The following examples illustrate the invention without restricting it limit.

The following abbreviations are used in the examples:
THF tetrahydrofuran
MeOH methanol
NBS N-bromosuccinimide
DMSO dimethyl sulfoxide
DMF dimethylformamide
AIBN azobisisobutyronitrile
Mp melting point

example 1 6- (4-chlorophenyl) -2,3-dihydro-1-methoxy-2,2-dimethyl-7-phenyl-1H- pyrrolizin-5-yl] carboxylic acid methyl ester a) 6- (4-chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1H- pyrrolizin-5-yl] carboxylic acid methyl ester

(6- (4-chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1H-pyrrolizine (10.0 g, 31.1 mmol, manufactured according to Laufer et al. (J. Med. Chem. 1994, 37, 1894-1897) and 3.3 g dry triethylamine are dissolved in 30 mL absolute THF, then a solution of 3.1 g (15.7 mmol) trichloromethyl chloroformate (diphosgene) in 20 mL THF is slowly added dropwise at RT and the mixture is stirred for 7 h. Then the 30 mL MeOH are added. The mixture is stirred for a further 12 h at RT. The product precipitates as a light green solid. It is suctioned off with the solvent and washed with a little MeOH. The mother liquor mixed with 200 mL water provides after ultrasound treatment (10 min ) a second crystal fraction The fractions thus obtained are purified by stirring with MeOH.
Overall yield: 9.94 g (84%), C ₂₃ H ₂₂ ClNO ₂ , 379.9 g / mol, mp. 170 ° C. -
IR (KBr): 1 / l (cm ^-1 ) = 2945, 1708 (CO ester), 1466, 1406, 1216, 1119, 1098, 831, 777, 702, 696.-
¹ H-NMR (CDCl ₃ ): d (ppm) = 7.26 - 7.11 (m, 7 H, ph + AA '), 6.99 - 6.94 (BB', 2 H), 4.14 (s, 2 H, CH ₂ ) , 3.65 (s, 3 H, OCH ₃ ), 2.84 (s, 2 H, CH ₂ ), 1.31 (s, 6 H, C (CH ₃ ) ₂ ).
¹³ C-NMR (CDCl ₃ ): d (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:
calc. C 72.72, H 5.84, N 3.69,
found C 72.57, H 5.78, N 3.64.

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

6- (4-Chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1H-pyrrolizin-5-yl] -carboxylic acid methyl ester (Example 1a, 4.0 g (10.5 mmol) are mixed with 2.3 g (13.0 mmol) NBS in CCl ₄ to the [1-bromo-6- (4-chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1H-pyrrolizin-5-yl] -carboxylic acid methyl ester The intermediate product is not isolated, but is reacted directly by adding 30 mL MeOH, a solid separates after a few minutes, the solvent is filtered off and the solid is washed with a little methanol.
Yield: 3.5 g (81%), C ₂₄ H ₂₄ ClNO ₃ , 409.9 g / mol,
M.p .: 121 ° C. -
IR (KBr): 1 / l (c ^-1 ) = 2981, 2956, 2900, 1698 (CO ester), 1455, 1438, 1312, 1217, 1135, 1083, 1012, 780, 703.-
¹ H-NMR (CDCl ₃ ): d (ppm) = 7.26 - 7.04 (m, 9 H, 2 ar.), 4.19 - 4.14 (m, 3H, 1-H + 3-H ₂ ), 3.66 (s, 3 H, COOC H ₃ ), 3.07 (s, 3 H, 1-OCH ₃ <, 1.32 (s, 3 H, 2-CH ₃ ), 1.21 (s, 3 H, 2-CH ₃ ).
¹³ C-NMR (CDCl ₃ ): d (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 (OCH ₃ ), 50.9 (COO C H ₃ ), 46.7 (C-2), 27.2, 20.5 (C ( C H ₃ ) ₂ ). -
CHN:
calc. 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-1H- pyrrolizine-5-yl carboxylic acid

6- (4-chlorophenyl) -2,3-dihydro-1-methoxy-2,2-dimethyl-7-phenyl-1H-pyrrolizin-5-yl] -carboxylic acid methyl ester (Example 1b, 3.5 g, 8.5 mmol) are in a solution of 3.0 g (53.5 mmol) KOH in 40 mL MeOH heated to reflux for 16 h. Then let cool and stir in 400 mL water, acidify with conc. HCl to pH 3 and extracted three times with 100 mL diethyl ether. The ether extracts are washed with water and dried over Na ₂ SO ₄ . It is filtered and concentrated until crystallization begins. The colorless solid is filtered off and dried.
Yield: 2.9 g (86%), C ₂₃ H ₂₂ ClNO ₃ , 395.9 g / mol,
M.p .: 195 ° C. -
IR (KBr): 1 / l (cm ^-1 ) = 2958, 2895 (OH acid), 1650 (CO acid), 1516, 1492, 1469, 1316, 1136, 1107, 1091.-
¹ H-NMR ([D ₆ ] -DMSO): d (ppm) = 7.29 - 7.11 (m, 7 lt Ph + AA '), 7.04 -7.00 (BB', 2 H), 4.26 (s, 1H, 1 -H), 4.12. and 3.98 (m, 2 H, AB system, 3-H ₂ , ² J = 12.0 H ₂ ), 2.97 (s, 3 H, OCH ₃ ), 1.22 (s, 3 H, 2- CH ₃ ), 1.14 (s, 3 H, 2-CH _3). -
¹³ C-NMR ([D ₆ ] -DMSO): d (ppm) = 161.6 (CO), 138.6, 134.3, 134.1, 131.1, 130.2, 132.5, 129.0, 128.1, 127.31, 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 ) ₂ ). -
CHN:
calc. 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-1H- pyrrolizine-5-yl carboxylic acid

6- (4-Chlorophenyl) -2,3-dihydro-1-methoxy-2,2-dimethyl-7-phenyl-1H-pyrrolizin-5-yl] -carboxylic acid (Example 2, 0.50 g, 1.26 mmol) are in 10 ml DMSO with approx. 10% water content dissolved and after adding 1.5 mL conc. HCl stirred at RT for 4 days. Then 30 mL of water are added. The crystals are freed from the solvent by suction and then taken up in 20 ml of diethyl ether. The organic phase is washed once with 20 mL water and dried over Na ₂ SO ₄ . After filtration, the solvent is spun off. The solid residue is purified by recrystallization from diethyl ether.
Yield: 0.10 g (21%), C ₂₂ H ₂₀ OClNO ₃ , 381.9 g / mol,
M.p .: 204 ° C. -
IR (KBr): 1 / l (cm ^-1 ) = 3510 (OH), 2954, 1639 (CO acid), 1468, 1313, 1139, 1102, 1091, 696.-
¹ H-NMR ([D ₆ ] -DMSO): d (ppm) = 7.33 - 7.05 (m, 9 H, 2 ar.), 5.55 (d, 1 H, OH, ³ J = 8.3 H ₂ ), 4.30 (d, 1 H, 1-H, ³ J = 8.3 Hz), 4.06 (m, 2 H, 3-H ₂ ), 1.17 (s, 3 H, 2-CH ₃ ), 1.02 (s, 3 H, 2-CH ₃ ). -
¹³ C-NMR ([D ₆ ] -DMSO): d (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:
calc. C 69.20, H 5.28, N 3.67,
found C 68.70, H 5.42, N 3.51.

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

Methyl 6- (4-chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1H-pyrrolizin-5-yl] -carboxylic acid (Example 1a, 8.0 g, 21.1 mmol) and 9.4 g (53 mmol ) NBS are refluxed in 40 mL CCl _{4 for} 3 h. Then 2.5 mL of water are added and the mixture is boiled under reflux for a further 16 h. The reaction mixture is concentrated to a residual volume of 5 ml and mixed with 40 ml of MeOH. It is crystallized at 4 ° C. The bright solid is suctioned off from the solvent and dried in vacuo.
Yield: 4.36 g (53%), C ₂₃ H ₂₀ ClNO ₃ , 393.9 g / mol,
M.p .: 233 ° C. -
IR (KBr): 1 / l (cm ^-1 ) = 2976, 2872, 1707, 1699 (CO ester + ketone), 1464, 1313, 1238, 1147, 1105, 692.-
¹ H-NMR (CDCl ₃ ): d (ppm) = 7.30 - 7.10 (m, 9 H, 2 ar.), 4.46 (s, 2 H, 3-H ₂ ), 3.73 (s, 3 H, OCH ₃ ), 1:39 (s, 6 H, 2-CH _3). -
¹³ C-NMR (CDCl ₃ ): d (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-1H- pyrrolizine-5-yl carboxylic acid

6- (4-chlorophenyl) -2,3-dihydro-1-oxo-2,2-dimethyl-7-phenyl-1H-pyrrolizin-5-yl-carboxylic acid methyl ester (Example 4, 4.4 g, 11.1 mmol) is added in one Solution of 3.0 g (53.5 mmol) KOH in 40 mL MeOH heated to reflux for 2 h. Then let cool and stir in 600 mL water. The cloudy solution is brought to pH 3 with concentrated hydrochloric acid. The precipitate separated by filtration and dried in a vacuum desiccator over phosphorus pentoxide.
Yield: 3.8 g (90%), C ₂₂ H ₁₈ ClNO ₃ , 379.9 g / mol,
Mp 284 ° C. -
IR (KBr): 1 / l (cm ^-1 ) = 2970, 170.7 (CO ketone), 1656 (CO acid), 1518, 1476, 1316, 1302, 1148, 1101, 699.-
¹ H-NMR ([D ₆ ] -DMSO): d (ppm) = 7.35 - 7.31 (AA ', 2 H), 7.20 - 7.10 (m, 7 H, Ph + BB'), 4.45 (s, 2 H , CH ₂ ), 1.26 (s, 6 H, 2-C H ₃ ). -
¹³ C-NMR ([D ₆ ] -DMSO): d (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 ) ₂ ). -
CHN:
calc. 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-1H- pyrrolizine

6- (4-chlorophenyl) -2,3-dihydro-2,2-dimethyl.-1-oxo-7-phenyl-1H-pyrrolizin-5-yl-carboxylic acid (Example 5, 2.0 g, 5.3 mmol) become 10 heated to melt for approx. 290 ° C. As soon as the gas evolution has ceased, the mixture is allowed to cool and the melt cake is treated in an ultrasonic bath with MeOH (30 min). Then the solvent is suctioned off and the light brown solid is dried.
Yield: 1.31 g (74%), C ₂₁ H ₁₈ ClNO, 335.13 g / mol,
Mp 261 ° C. -
IR (KBr): 1 / l (cm ^-1 ) = 3116 (CH), 2970 (CH), 1684 (CO ketone), 1529, 1350, 1092, 1016, 821, 698, 534. -
¹ H-NMR (CDCl ₃ ): d (ppm) = 7.47 - 7.10 (m, 9 H, 2 Ar.), 7.09 (s, 1 H, 5-H), 4.14 (s, 2H, 3-H ₂ ), 1:37 (s, 6H, _2-CH3). -
¹³ C-NMR (CDCl ₃ ): d (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:
calc. 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-1H- pyrrolizine

6- (4-chlorophenyl) -2,3-dihydro-2,2-dimethyl-1-oxo-7-phenyl-1H-pyrrolizine (Example 6, 0.30 g, 0.9 mmol) are suspended in THF. 0.04 g (1.1 mmol) of LiAlH ₄ is added and the mixture is heated under reflux for 0.5 h. Then the mixture is allowed to cool and excess hydride is decomposed by adding 10 mL saturated NaHCO ₃ solution. Then 10 mL 10 percent. NaOH added and the organic phase separated. The aqueous phase is extracted three times with 10 mL diethyl ether. The organic extracts are dried over Na ₂ SO ₄ , filtered and evaporated. The product foams in a vacuum. Residual solvent is removed in vacuo at 40 ° C.
Yield: 0.28 g (96%), C ₂₁ H ₂₀ ClNO, 337.9 g / mol -
IR (KBr): 1 / l (cm ^-1 ) = 3336 (b), 2958, 2870, 1601, 1525, 1486, 1409, 1173, 1092, 1032, 1012, 833, 767, 700.-
¹ H NMR (CDCl ₃ ): d (ppm) = 7.35 - 7.12 (m, 9 H, 2 ar.), 6.71 (s, 1 H, 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 H ₂ ), 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 ): d (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:
calc. 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-1H- pyrrolizine-5-yl carbaldehyde

6- (4-chlorophenyl) -2,3-dihydro-2,2-dimethyl-1-oxo-7-phenyl-1H-pyrrolizine (Example 6, 0.30 g (0.9 mmol) are suspended in 1 mL DMF sus The suspension is cooled to 5 ° C. 0.28 g (1.8 mmol) of POCl _{3 is} then added, and the mixture is stirred at RT for 30 min and then heated for 16 h to 80 ° C. The cooled reaction mixture is hydrolyzed with 10 mL of 10 percent sodium hydroxide solution and extracted twice with 20 mL methylene chloride The organic extracts are washed three times with 40 mL water, dried over Na ₂ SO ₄ , filtered and rotated in. The crude product is recrystallized from ethanol.
Yield: 250 mg (76%), C ₂₂ H ₁₈ ClNO ₂ , 363.8 g / mol,
Mp 185 ° C. -
IR (KBr): 1 / l (cm ^-1 ) = 2962, 2868, 1716 (CO aldehyde), 1662 (CO Ke ton), 1514, 1458, 1406, 1381, 1118, 1014, 845, 746, 723.-
¹ H-NMR (CDCl ₃ ): d (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 ): d (ppm) = 196.9 (CO), 18.1.7 (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:
calc. C 72.63, H 4.99, N 3.85,
found C 72.34, H 5.22, N 3.80.

Example 9 1-acetoxy-6- (4-chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1H- pyrrolizin-5-yl acetic acid tert-butyl ester a) 6- (4-chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1H- pyrrolizin-5-yl-acetic acid tert-butyl ester

6- (4-chlorophenyl) -2,3-dihydro-1-hydroxy-2,2-dimethyl-7-phenyl-1H-pyrrolizin-5-yl] acetic acid (ML3000, 10.0 g, 26.3 mmol), Herge produces according to Laufer et al. (J. Med. Chem. 1994, 37, 1894-1897) are dissolved in 40 mL absolute THF and 5.1 g (31.5 mmol) carbonyldiimidazole are added. The mixture is stirred for 30 min until the imidazolide precipitates at RT, then 80 ml of tert-butanol are added and the water is heated to 100 ° C. As soon as the THF has completely distilled over, the reaction mixture is heated at 110 ° C. for a further 7 days. Then allowed to cool and stirred with 80 mL diethyl ether or MeOH. The crystals are freed from the solvent by suction and dried. Additional crystals can be obtained from the mother liquor by spinning in and precipitation with MeOH.
Yield: 8.0 g (70%), C ₂₇ H ₃₀ ClNO ₂ 436.0 g / mol,
M.p .: 168 ° C. -
IR (KBr): 1 / l (cm ^-1 ) = 2954, 2870.1728 (CO ester), 1487, 1379, 1163, 1151, 1097, 822, 700.
¹ H-NMR (CDCl ₃ ): d (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, (CC H ₃ ) ₃ ), 1.29 (s, 6 H, 2-CH ₃ ). -
¹³ C-NMR (CDCl ₃ ): d (ppm) = 170.1 ( C O), 1.36.1, 134.8, 133.9, 131.5, 131.6, 128.2, 128.1, 128.0, 124.6, 118.4, 114.6, 81.2 (O C (CH ₃ ) ₃ ), 58.3 (CH ₂ ), 43.3 (C-2), 40.5 (CH ₂ ), 32.9 (CH ₂ ), 28.1 (OC ( C H ₃ ) ₃ ), 28.0 (C ( C H ₃ ) ₂ ).
CHN:
calc. 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-1H- pyrrolizin-5-yl-acetic acid tert-butyl ester

Tert-Butyl 6- (4-chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1H-pyrrolizin-5-yl-acetic acid (Example 9a, 5.0 g, 11.5 mmol) and NBS ( 2.2 g, 12.4 mmol) are mixed with 50 mL CCl ₄ and a spatula tip AIBN. The reaction mixture is heated to 50 ° C. for 45 minutes. After cooling, the succinimide is separated off by filtration 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 / l (cm ^-1 ) = 2968, 2931 (s, aliphatic CH), 1730 (s, broad, CO, ester), 1466, 1367, 1147, 1099, 833, 787, 770 ( s, C-Br). -
¹ H-NMR (CDCl ³ ): d (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, broad, 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, broad, 6 H, 2 CH ₃ ). -
¹³ C-NMR (CDCl ₃ ): d (ppm) = 169.5 (CO), 134.8, 133.9, 133.5, 132.0,131.7, 128.9, 128.3, 128.1 ,. 125.6, 1.24.3, 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 ) ₂ ).

c) 1-acetoxy-6- (4-chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl- 1H-pyrrolizin-5-yl acetic acid tert-butyl ester

1-Bromo-6- (4-chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1H-pyrrolizin-5-yl-acetic acid tert-butyl ester (Example 9b, 1.15 g, 2.23 mmol ) 0.5 g of potassium acetate, 70 ml of absolute diethyl ether and 3 drops of acetic acid are added and the mixture is heated under reflux for 3 h. Then allowed to cool, the inorganic salts are filtered off and the ether solution is rotated in. With a residual volume of approx. 5 mL, 10 mL hexane are added. After rubbing, the product precipitates and is separated off by suctioning off the solvent.
Yield 0.74 g (65%) C ₂₉ H ₃₂ ClNO ₄ ; 494.0 g / mol,
M.p .: 81 ° C. -
IR (KBr): 1 / l (cm ^-1 ) = 2972, 1728 (CO ester), 1368, 1246, 1149, 1014, 833, 708.-
¹ H-NMR (CDCl ₃ ): d (ppm) = 7.24 - 6. 99 (m, 9 H, 2.Ar.), 5.92 (s, 1 H, 1-H), 3.92 and 3.7 5 (2 H , AB, 3-H ₂ , ² J = 10.4 H ₂ ), 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 ): d (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:
calc. 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-1H- pyrrolizin-5-yl] -2-oxoacetic acid ethyl ester; a) 1-bromo-6- (4-chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1H- pyrrolizin-5-yl-2-oxo-acetic acid ethyl ester

6- (4-Chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1H-pyrrolizin-5-yl] -2-oxoacetic acid ethyl ester (9.82 g, 2.3.3 mmol), prepared according to Ref. are dissolved in 50 mL CCl ₄ . Then 4.70 g (26.4 mmol) of NBS and a spatula tip of azoisobutyronitrile (AIBN) are added and the mixture is heated under reflux for 4 h. After the reaction mixture has cooled, the succinimide is filtered off and the clear solution is spun in. The residue crystallizes from diisopropyl ether.
Yield: 8.9 g (76%), C ₂₅ H ₂₃ BrClNO ₃ , 500.8 g / mol.
Mp 167 ° C. -
IR (KBr): 1 / l (cm ^-1 ) = 2966 (CH), 1740 (CO ester), 1630 (CO a-ketone), 1446, 1433, 1257, 1068, 1018, 851, 696.-
¹ H-NMR (CDCl ₃ ): d (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 H ₂ ). -
¹³ C-NMR (CDCl ₃ ): d (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 (CH ₂ ) , 59.0 (CH ₂ ), 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:
calc. C 59.96, H 4.63, N 2.80,
found C 59.95, H 4.64, N 2.74.

b) 1-acetoxy-6- (4-chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl- 1H-pyrrolizin-5-yl-2-oxoacetic acid ethyl ester

1-bromo-6- (4-chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1H-pyrrolizin-5-yl-2-oxo-acetic acid ethyl ester (Example 10a, 10.0 g 20 mmol) are dissolved in 50 mL DMF. After adding potassium acetate (5.0 g, 51 mmol), the mixture is heated to 80 ° C. for 2 h. The cooled reaction mixture is poured onto ice and extracted with 200 mL diethyl ether. The ether phase is separated off, washed twice with 150 ml of water, dried over Na ₂ SO ₄ , filtered and evaporated down.

A mixture of 1-acetoxy-6- (4-chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1H-pyrrolizin-5-yl-2-oxoacetic acid ethyl ester and 2- [6- (4-Chlorophenyl) -2,3-dihydro-1-hydroxy-2,2-dimethyl-7-phenyl-1H-pyrrolizin-5-yl-2-oxoacetic acid, ethyl ester.
Yield: 6.9 g (75%) of a mixture with changing proportions of the two components. Separation of the components using SC (silica gel 60, ether / cyclohexane 1: 1) provides:
2- [1-Acetoxy-6- (4-chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1H-pyrrolizin-5-yl-2-oxoacetic acid, ethyl ester
C ₂₇ H ₂₆ ClNO ₅ , 480.0 g / mol:
Mp 142 ° C -
IR (KBr): 1 / l (cm ^-1 ) = 2970 (CH), 1747 (CO ester), 1624 (CO a-ketone), 1448, 1427, 1227, 1084, 1018, 733, 696.-
¹ H-NMR (CDC ₃ ): d (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 CNMR (CDCl ₃ ): d (ppm) = 177.4 (CO a-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 (CH ₂ ), 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:
calc. 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-1H- pyrrolizin-5-yl-2-oxoacetic acid ethyl ester

according to SC from example 10b:
C ₂₅

H ₂₄

ClNO ₄

, 438.0 g / mol. -
M.p .: 193 ° C. -
IR (KBr): 1 / l (cm ^-1

) = 3520 (OH), 2958 (CH), 1730 (CO ester), 1622 (CO a-ketone), 1450, 1425, 1269, 1076, 1016, 737, 700.
¹

H-NMR (CDCl ₃

): d (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

, ^2nd

J = 9.8 Hz), 3.75 - 3.50 (m, 2 H, ABX ₃

, OCH ₂

), 1.96 (d, 1H, OH, ^3rd

J = 5.8 Hz), 1.32 (s, 3 H, 2-CH ₃

), 1.20 (s, 3 H, 2-CH ₃

; 1, 1.07 (t, 3 H, OCH ₂

C H ₃

, ^3rd

J = 7.2 Hz). -
¹³

C-NMR (CDCl ₃

): d (ppm) = 177.5 ( C

O a-ketone), 164.3 ( C

O 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-1H- pyrrolizine-5-yl acetic acid

1-Acetoxy-6- (4-chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1H-pyrrolizin-5-yl-acetic acid tert-butyl ester (Example 9c, 1.00 g, 2.0 mmol ) is dissolved in 10 mL MeOH. 0.5 g of KOH is added and it is heated under reflux until the intermediate precipitate has dissolved. Then let cool and stir in 600 mL water. The cloudy solution is with conc. HCl brought to pH 3. It is extracted three times with 100 mL diethyl ether each. The Etherex tracts are washed twice with water and dried over Na ₂ SO ₄ , filtered and evaporated. A mixture of 6- (4-chlorophenyl) -2,3-dihydro-1-hydroxy-2,2-dimethyl-7-phenyl-1H-pyrrolizin-5-yl-acetic acid and 2- [6- (4th -Chlorphenyl) -2,3-dihydro-1-methoxy-2,2-dimethyl-7-phenyl-1H-pyrrolizin-5-yl] acetic acid (see Example 16).

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

A product mixture which is a 1: 2 mixture of 2- [1-acetoxy-6- (4-chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1H-pyrrolizin-5-yl] - Contains 2-oxoacetic acid ethyl ester and 2- [6- (4-chlorophenyl) -2,3-dihydro-1-hydroxy-2,2-dimethyl-7-phenyl-1H-pyrrolizin-5-yl] -2-oxoacetic acid ethyl ester ( from Example 10b, 1.50 g, 3.31 mmol) is suspended in 15 mL diethylene glycol, 1.3 mL hydrazine hydrate (80 percent) is added and the mixture is heated to 80 ° C. for 1 h. Then let cool and add 2.5 g of KOH. The mixture is then heated to 130 ° C. for 1 hour and to 160 ° C. for 2 hours. After cooling, dilute with 30 mL water and concentrate with conc. HCl brought to pH 2 and extracted three times with 30 mL diethyl ether. The organic extracts are washed twice with 50 mL water, dried over Na ₂ SO ₄ , filtered and rotated to a residual volume of 50 mL. Then add about 20 mL hexane and evaporate until crystallization begins. The crystals are separated by suction, the solution is further concentrated. In this way, several crystals fractions are obtained. The last crystals contain the desired compound.
Yield: 0.07 g (6%) C ₂₃ H ₂₂ ClNO ₃ , 395.9 g / mol. -
IR (KBr): 1 / l (cm ^-1 ) = 3421 (OH), 2958, 2926, 2870 (OH), 1730 (CO acid), 1485, 1090, 1012, 831, 700.-
¹ H-NMR (CDCl ₃ ): d (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-CH ₃ ).

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

1-Bromo-6- (4-chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1H-pyrrolizin-5-yl] acetic acid tert-butyl ester (Example 9b, 1.15 g, 2.23 mmol) are dissolved in 10 mL MeOH. A solid separates after a few minutes. The solvent is suctioned off and the solid is washed with a little MeOH.
Yield: 0.73 g (70%), C ₂₈ H ₃₂ ClNO ₃ , 466.0 g / mol,
M.p .: 140 ° C. -
IR (KBr): 1 / l (cm ^-1 ) = 2881, 1728 (CO ester), 1153, 1369, 1342, 1214, 1089, 827, 746, 698. - ¹ H-NMR (CDCl ₃ ): d ( 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 ): d (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 ) ₂ ). -
CHN:
calc. 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-1H- pyrrolizine-5-yl acetic acid

6- (4-Chlorophenyl) -2,3-dihydro-1-methoxy-2,2-dimethyl-7-phenyl-1H-pyrrolizin-5-yl-acetic acid tert-butyl ester (Example 13, 1.00 g, 2.14 mmol ) is suspended in 10 mL MeOH. 0.5 g of KOH is added and the mixture is heated under reflux for 2 h. Then let cool and stir in 600 mL water. The cloudy solution is with conc. HCl brought to pH 3. It is extracted three times with 100 mL diethyl ether each. The ether extracts are washed twice with water and dried over Na ₂ SO ₄ . It is filtered and rotated until the start of crystallization. The colorless solid is freed of residual solvent by suction and dried.
Yield: 0.66 g (75%), C ₂₄ H ₂₄ ClNO ₃ , 409.9 g / mol,
M.p .: 168 ° C. -
IR (KBr): 1 / l (cm ^-1 ) = 3034 (CH), 2966, 2884 (OH), 1716 (CO acid), 1092, 1456, 1225, 1206, 1016, 697.-
¹ H-NMR ([D ₆ ] -DMSO): d (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): d (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:
calc. 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- 1H-pyrrolizine

6- (4-chlorophenyl) -2,3-dihydro-1-methoxy-2,2-dimethyl-7-phenyl-1H-pyrrolizin-5-yl-acetic acid (Example 14, 0.50 g, 1.22 mmol) is added in one Mixture of 5 mL DMSO and 1 mL water suspended and heated to 90-100 ° C for 4 h. After the reaction mixture has cooled, 30 ml of diethyl ether are added, the aqueous phase is separated off and the ether solution is washed three times with 50 ml of water. After drying over Na ₂ SO ₄ and filtration, the mixture is concentrated in vacuo. The residue is crystallized from cyclohexane.
Yield: 0.26 g (60%), C ₂₂ H ₂₂ ClNO, 351.9 g / mol,
M.p .: 133 ° C. -
IR (KBr): 1 / l (cm ^-1 ) = 3302 (OH), 2956, 2906, 1486, 1381, 1054, 999, 831, 732, 699.-
¹ H-NMR (CDCl ₃ ): d (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): d (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 (% rel. Int.), 352 (11, (M + H) ⁺ ), 334 (100). -
CHN:
calc. 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- 1H-pyrrolizine

6- (4-chlorophenyl) -2,3-dihydro-1-hydroxy-2,2,5-trimethyl-7-phenyl-1H-pyrrolizine (Example 15, 0.38 g, 1.08 mmol) is dissolved in 10 mL MeOH. The clear solution is briefly treated with HCl gas until a light precipitate is formed. The mixture is then diluted with 10 mL MeOH and the solid is separated off by suctioning off the solvent. Wash again several times with MeOH and allow to air dry.
Yield: 0.30 g (76%), C ₂₃ H ₂₄ ClNO, 365.9 g / mol,
M.p .: 179 ° C. -
IR (KBr): 1 / l (cm ^-1 ) = 2980, 2935, 2878, 1484, 1463, 1380, 1317, 1181, 1087, 819, 766, 750, 696.-
¹ H-NMR (CDCl ₃ ): d (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 ): d (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:
calc. 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-1H- pyrrolizin-5-yl] acetic acid tert-butyl ester

Tert-Butyl 6- (4-chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1H-pyrrolizine-5-yl-acetic acid (Example 9a, 15.0 g, 34.4 mmol) and NBS ( 13.5 g, 75.8 mmol) are suspended in 75 mL CCl ₄ . 5 mL of water are added and the mixture is heated to: 70 ° C. for 2.5 h. The cooled reaction mixture is dried over Na ₂ SO ₄ , filtered and the solvent is spun off. The residue crystallizes from MeOH at 5 ° C. The solvent is suctioned off and the crystals are washed with ice-cold MeOH.
Yield: 9.0 g (58%). C ₂₇ H ₂₈ ClNO ₃ ; 450.0 g / mol,
M.p .: 180 ° C. -
IR (KBr): 1 / l (cm ^-1 ) = 1728 (CO ester), 1686 (CO ketone), 1541, 1365, 1294, 1144, 1095, 1014, 833, 694.-
¹ H-NMR (CDCl ₃ ): d (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 ): d (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:
calc. 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-1H- pyrrolizine-5-yl acetic acid

6- (4-Chlorophenyl) -2,3-dihydro-2,2-dimethyl-1-oxo-7-phenyl-1H-pyrrolizin-5-yl] acetic acid tert-butyl ester (Example 17, 14.0 g, 31.1 mmol) is added to a solution of 15.0 g KOH in 180 mL MeOH and heated to reflux for 2 h, allowed to cool and stirred in 600 mL water. The solution is with conc. HCl brought to pH 3 and extracted with 100 mL diethyl ether. The ether extract is washed with water and dried over sodium sulfate. Filtrate and reduce the volume 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,
M.p .: 234.3 ° C. -
IR (KBr): 1 / l (cm ^-1 ) = 2968, 2926 (CH), 1743 (CO acid), 1650 (CO ketone), 1534, 1364, 1330, 1172, 1107, 696.-
¹ H-NMR ([D ₆ ] -DMSO): d (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 CNMR ([D ₆ ] -DMSO): d (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 (CH ₂ ), 48.9 (C-2), 30.6 (CH ₂ ), 24.4 (C ( C H ₃ ) 2). -
CHN:
calc. 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-1H- pyrrolizine

6- (4-chlorophenyl) -2,3-dihydro-2,2-dimethyl-1-oxo-7-phenyl-1H-pyrrolizin-5-yl-acetic acid (Example 18, 0.60 g, 1.52 mmol) is stirred for 15 min heated to 245 ° C. The cooled melt is ground and extracted with 10 mL diethyl ether. The solvent is suctioned off and the crystals are dried.
Yield: 420 mg (79%). C ₂₂ H ₂₀ ClNO, 349.9 g / mol,
Mp 227 ° C. -
IR (KBr): 1 / l (cm ^-1 ) = 2966, 2866, 1682 (CO), 1537, 1461, 1399, 1359, 1322, 1125, 1089, 753, 695.-
¹ H-NMR (CDCl ₃ ): d (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 ): d (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:
calc. C 75.53, H 5.76, N 4.00,
found C 75.58, H 5.84, N 4.13.

Example 20 2- [6- (4-chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1H- pyrrolizin-5-yl] -2-hydroxyacetic acid ethyl ester

6- (4-Chlorophenyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1H-pyrrolizin-5-yl] -2-oxoacetic acid ethyl ester (1.0 g, 2.4 mmol), prepared according to Laufer et al. (J. Med. Chem. 1994, 37, 1894-1897) is dissolved in 10 mL THF. Then add a solution of 0.03 g NaBH ₄

in 3 mL water and stir the 2-phase system for 1 h at RT. Then it is concentrated with 3 mL. NH ₃

-Solution added and stirred again for 1 h. The organic phase is separated off, diluted with about 80 ml of water and extracted twice with 20 ml of diethyl ether. The ether phase is washed three times with 100 mL water, over Na ₂

SO _4th

dried and not spun in to dryness. The product crystallizes after the addition of 10 mL hexane.
Yield: 0.86 g (86%), C ₂₅

H ₂₆

ClNO ₃

, 423.9 g / mol,
M.p .: 117 ° C. -
IR (KBr): 1 / l (cm ^-1

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

H-NMR ([D ₆

] -DMSO): d (ppm) = 7.38 - 7.39: (AA ', 2 H), 7.19 - 7.00 (m, 5 H, Ph), 6.99 - 6.95 (BB', 2 H), 5.93. (d, 1H, OH, ^3rd

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

, ^2nd

J = 11.0 Hz), 2.82 and 2.68 (2 H, AB, 1-H ₂

, ^2nd

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

, ^3rd

J = 7.1 H ₂

). -
¹³

CNMR ([D ₆

] -DMSO): d (ppm) = 171.6 ( C

O), 135.5, 134.9, 134.3, 130.7, 131.7, 128.1, 128.0, 127.7, 124.7, 122.8, 122.7, 113.6, 64.8 ( C

HOH), 60.7 (CH ₂

), 58.8 (CH ₂

), 42.8 (C-2), 39.4 (CH ₂

), April 27 (CH ₃

), 27.1 (CH ₃

), 14.0 (OCH ₂ C

H ₃

). -
CHN:
calc. C 70.83, H 6.18, N 3.30,
found C 71.24, H 6.38, N 3.07.

Example 21 6- (2-benzofuranyl) -2,3-dihydro-2,2-dimethyl-1-methoxy-7-phenyl-1H- pyrrolizin-5-yl-2-oxoacetic acid ethyl ester a) 6- (2-Benzofuranyl) -1-bromo-2,3-dihydro-2,2-dimethyl -7-phenyl-1H- pyrrolizin-5-yl-2-oxoacetic acid ethyl ester

6- (2-Benzofuranyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1H-pyrrolizin-5-yl-2-oxoacetic acid ethyl ester (4.3 g, 10 mmol, Laufer et al. Arch. Pharm. Pharm. Med. Chem. 1997, 330, 307-312.) And NBS (2.0 g, 11 mmol) are refluxed with AIBN (100 mg) in CCl ₄ (100 mL) for 2 h. The suc cinimid is filtered off from the cooled mixture and the solvent is removed in vacuo and crystallized from diethyl ether.
Yield 4.5 g (89%), C ₂₇ H ₂₄ BrNO ₄ , 506.41 g / mol
IR (KBr): 1 / l (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): d (ppm) = 7.47 - 7.20 (m, 9H, 2 ar.), 6.52 (s, 1H, 3-CH furan); 4.97 (s, 1H, CH); 4.38 - 4.13 (AB, 2H, CH ₂ ), 3.75-3.68 (m, 2H, CH ₂ ), 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): d (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) 6- (2-benzofuranyl) -2,3-dihydro-2,2-dimethyl-1-methoxy-7-phenyl- 1H-pyrrolizin-5-yl-2-oxoacetic acid ethyl ester

6- (2-Benzofuranyl) -1-bromo-2,3-dihydro-2,2-dimethyl-7-phenyl-1H-pyrrolizin-5-yl-2-oxoacetic acid ethyl ester (Example 21a, 1.52 g, 3 mmol ) is in abs. MeOH (40 mL) suspended and stirred at RT for 30-45 min until a fine precipitate is formed. 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 / l (cm ^-1 ) = 1754 (CO) 1720, 1661, 1458, 1440, 1431, 1425, 1251, 1187, 1179, 1094, 1088, 1063, 756.
¹ HNMR ([D ₆ ] -DMSO): d (ppm) = 7.57 - 7.23 (m, 9H, 2 ar.); 6.73 (s, 1H, CH); 4.38 (s, 1H, CH); 4:15 to 4:13 (m, 2H, CH _2); 3.60 - 3:55 (s, 2H, CH _2); 3:02 (s, 3H, CH _3); 1.24 (s, 3H, CH _3); 1.18 (s, 3H, CH _3); 0.94 - 0.87 (t, 3H, CH ₃ )
besides little
6- (2-Benzofuranyl) -2,3-dihydro-2,2-dimethyl-1-methoxy-7-phenyl-1H-pyrrolizin-5-yl-2-oxoacetic acid, methyl ester
C ₂₇ H ₂₅ NO ₅ , 443.50 g / mol,
¹ HNMR (CDCl ₃ ): d (ppm) = 7.55-7.10 (m, 9H, 2 ar.); 6.49 (s, 1H, 3-CH furan); 4.21 (s, 2H, CH _2); 4.18 (s, 1H, CH); 3:35 (s, 3H, CH _3); 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 the 3-CH ₂ group

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

Ethyl 6- (2-benzofuranyl) -1-bromo-2,3-dihydro-2,2-dimethyl-7-phenyl-1H-pyrrolizin-5-yl-2-oxoacetate (Example 21a, 1.1 g, 2 mmol) are suspended in a methanolic NaOH prepared from Na (0.52 g, 20 mmol) in MeOH (40 mL) and boiled under reflux for 2 h. After removing the solvent i. vac. the residue is distributed in water and neutral compounds are extracted with ethyl acetate and discarded. The water phase acidified with HCl (10%) to pH 3 is extracted again with ethyl acetate. The organic phase of the acidic compounds, dried (Na ₂ SO ₄ ) and concentrated.
Yield: 0.65 g (77%), C ₂₆ H ₂₃ NO ₅ , 429.48 g / mol,
IR (KBr): 1 / l (cm ^-1 ) = 3430, 2959, 2939, 1721 (CO acid), 1621 (sh), 1608, 1458, 1446, 1369, 1272, 1254, 1081, 1072, 1064, 752 . -
¹ HNMR ([D ₆ ] DMSO): d (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, CH ₂ ); 3:00 (s, 3H, CH _3); 1.24 (s, 3H, CH _3); 1.17 (s, 3H, CH ₃ ), in CDCl ₃ : no splitting of the methylene group at the 3-position
¹³ C NMR (CDCl ₃ ): d (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; B2.0; 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-1H- pyrrolizine-5-yl acetic acid

Ethyl 6- (2-benzofuranyl) -2,3-dihydro-2,2-dimethyl-1-methoxy-7-phenyl-1H-pyrrolizin-5-yl-2-oxoacetate (Example 21b, 0.92 g, 2 mmol ) in diethylene glycol (20 mL) with hydrazine hydrate 80% (1.56 mL, 40 mmol) for 30 min. heated to 60 ° C, then with KOH techn. 85% (2.1 g, 32 mmol) were added and the mixture was kept at 130 ° C. for 4 h (until the evolution of gas had ceased and the color had faded). The mixture poured onto ice is brought to pH 3 with 10% HCl, the fine precipitate which is formed is filtered off with suction and dried over P ₂ O ₅ .

For the purification, the crude acid (1.0 g) is adsorbed on neutral Al ₂ O ₃ , impurities are removed by elution with diethyl ether, then desorbed with a saturated NaH ₂ PO ₄ solution and taken up in ether. The filtered ether extract was evaporated to dryness.
Yield: 0.45 g, C ₂₆ H ₂₅ NO ₄ , 415.49 g / mol.
¹ HNMR ([D ₆ ] DMSO): d (ppm) = 12.6 (b, 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 CH ₂ ), 2.95 (s, 3H, OCH ₃ ); 1.24 (s, 3H, CH _3); 1.13 (s, 3H, CH _3).
¹³ CNMR (CDCl ₃ ): d (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- 1H-pyrrolizin-5-yl] -2-hydroxy-acetic acid

From ethyl 2- [6- (2-benzofuranyl) -2,3-dihydro-2,2-dimethyl-7-phenyl-1H-pyrrolizin-5-yl] -2-oxoacetate (S. Laufer, et al. Arch. Pharm. Pharm Med. Chem. 1997, 330, 307-312) according to the method described in Example 20.
Yield: 0.28 g (65%) crystallized from diethyl ether, C ₂₇ H ₂₇ NO ₄ , 429.52.
IR (KBr): 1 / l (cm ^-1 ) = 3431, 2958.1730 (CO ester), 1603, 1454, 1369, 1254, 1164, 1065, 1024, 751, 700.
¹ HNMR (CDCl ₃ ): d (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 _AB = 10.6 Hz, CH ₂ ), 3.39 (d, OH, J = 2.0 Hz), 2.80 / 2.67 (AB, 2H, CH ₂ , J _AB = 15 Hz); 1.35 - 1.15 (2 s + t, 9H, C (CH ₃ ) ₂ , OCH ₂ C H ₃ ).
¹³ C NMR (CDCl ₃ ): d (ppm) = 172.9; 154.4; 1.52.1, 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

Claims (10)

1. Pyrrolizine compounds of the formula I. wherein
R1 and R2, which may be the same or different, represent aryl or an aromatic mono- or bicyclic, heterocyclic radical which has 1, 2 or 3 heteroatoms which are selected independently of one another under N, O and S. where the Residues R1 and R2 are optionally substituted by 1, 2 or 3 groups which are selected independently from one another from alkyl, halogen CF ₃ , alkoxy, aryloxy and CN and can optionally be fused with phenyl or naphthyl;
R3 is H, alkyl, COOH, COOalkyl, COOAlkPhenyl, COCOOH, COCOOalkyl, CHO or AY, where
A represents C ₁ -C ₈ alkylene or C ₂ -C ₈ alkenylene, which may optionally be substituted by hydroxyl or alkoxy,
Y represents COOH, SO ₃ H, OPO (OH) ₂ , OP (OH) ₂ , tetrazolyl, COOAl kyl, SO ₃ alkyl, CHO or OH;
Alk represents C ₁ -C ₄ alkylene;
R4, R5, R6 and R7, which may be the same or different, are H or alkyl;
one of the radicals R8 and R9 represents H or alkyl and the other represents hydroxyl, alkoxy or acyloxy or R8 and R9 together with the carbon atom to which they are attached represent a carbonyl group,
and the optical isomers, physiologically acceptable salts and physiologically readily hydrolyzable esters thereof. 2. Compounds according to claim 1 of formula I, wherein R3 is H, alkyl, COOH, CHO or AY, where A is C ₁ -C ₈ -alkylene, which is optionally substituted by OH, and Y is COOH, SO ₃ H , OPO (OH) ₂ , CHO or tetrazolyl. 3. Compounds according to claim 1 or 2 of formula I, wherein R3 is H, alkyl, COOH, CHO or AY, where A is C ₁ -C ₈ -alkylene, which is optionally substituted by OH, and Y is COOH. 4. Compounds according to any one of the preceding claims of formula I, wherein R1 and R2, which may be the same or different, are aryl or a 5- or 6-membered heterocyclic, aromatic radical, where R1 and R2 are 1 or independently Can have 2 halogen and / or CF ₃ substituents and wherein the heterocyclic radical can be condensed with a phenyl group. 5. Compounds according to claim 4 of formula I, wherein R1 and R2, which may be the same or different, for phenyl, with 1 or 2 halogen atoms substituted phenyl, thienyl or Benzofuranyl stand. 6. Compounds according to claim 4 of formula I, wherein R1 for Phenyl and R2 for monohalogen-substituted phenyl or Benzofuranyl stand.   7. Compounds according to one of the preceding claims of For mel I, wherein R8 and R9 together with the carbon atom that they are bound represent a carbonyl group. 8. Pharmaceutical composition containing at least one verb manure according to one of claims 1 to 7, optionally together men with pharmaceutically acceptable carrier and / or additive fabrics. 9. Use of at least one connection according to one of the claims che 1 to 7 for the preparation of a pharmaceutical agent for the prevention of allergy-induced diseases or for the treatment of diseases of the rheumatic type ses.