DOPAMINE-B-HYDROXYLASE INHIBITORS

Abstract

This invention relates to: (a) compounds of Formula Ia (with R1, R4, R5, R6, n and A as defined herein) and pharmaceutically acceptable salts or solvates thereof that are useful as dopamine--hydroxylase inhibitors; (b) pharmaceutical compositions comprising such compounds, salts or solvates; (c) the use of such compounds, salts or solvates in therapy; (d) therapeutic methods of treatment using such compounds, salts or solvates; and (e) processes and intermediates useful for the synthesis of such compounds.

##STR00001##

Claims

1. A compound of formula Ia, or a pharmaceutically acceptable salt or solvate thereof: ##STR00090## wherein: R.sub.1 is hydrogen, C.sub.1-C.sub.6 alkyl, partially or fully deuterated C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.2-C.sub.6 cyanoalkyl, C.sub.1-C.sub.6 mercaptoalkyl or amino; R.sub.4 is hydrogen or C.sub.1-C.sub.3 alkyl; R.sub.5 is hydrogen or C.sub.1-C.sub.2 alkyl; or R.sub.4 and R.sub.5 combine, together with the carbon atom to which they are attached, to form a cyclopropyl ring wherein the CH.sub.2 moiety is optionally substituted with two deuterium atoms; R.sub.6 is C.sub.1-C.sub.6 alkyl or partially or fully deuterated C.sub.1-C.sub.6 alkyl; A is C.sub.5-C.sub.7 cycloalkyl, furanyl, thiophenyl, methylthiophenyl or ##STR00091## wherein: X.sub.1 is hydrogen, halo or methyl; X.sub.1 is hydrogen or halo; X.sub.2 is hydrogen, halo or methyl; X.sub.2 is hydrogen or halo; X.sub.3 is hydrogen or fluoro; n is 0 or 1, and when n is 0 a single bond joins the carbon atoms to which the CH.sub.2 moeity would be attached when n is 1.

2. A compound according to claim 1, wherein n is 0.

3. A compound according to claim 1, wherein R.sub.4 and R.sub.5 combine, together with the carbon atom to which they are attached, to form a cyclopropyl ring wherein the CH.sub.2 moiety is optionally substituted with two deuterium atoms.

4. A compound according to claim 1, wherein more than 50% of substituents R.sub.5 and A have the stereochemical configuration of formula Id ##STR00092##

5. A compound according to claim 1, wherein more than 50% of substituents R.sub.5 and A have the stereochemical configuration of formula Ie ##STR00093##

6. A compound according to claim 1, wherein A is ##STR00094## wherein X.sub.1, X.sub.1, X.sub.2, X.sub.2 and X.sub.3 are as defined in claim 1.

7. A compound according to claim 1, wherein R.sub.1 is hydrogen, methyl, d3-methyl, propyl, cyclopropyl, cyanomethyl, mercaptoethyl or amino.

8. A compound according to claim 1, wherein R.sub.4 is hydrogen or methyl.

9. A compound according to claim 1, wherein R.sub.5 is hydrogen or methyl.

10. A compound according to claim 1, wherein R.sub.6 is methyl, n-butyl or d.sub.3-methyl;

11. A compound according to claim 1, wherein A is ##STR00095## wherein: X.sub.1 is hydrogen, fluoro, chloro or methyl; X.sub.1 is hydrogen, fluoro or chloro; X.sub.2 is hydrogen, fluoro, chloro, bromo or methyl; X.sub.2 is hydrogen, fluoro, chloro or bromo; X.sub.3 is hydrogen or fluoro.

12-14. (canceled)

15. A method for treating or preventing conditions ameliorated by inhibition of dopamine-beta-hydroxylase comprising administering a therapeutically effective amount of a compound of formula Ia, as defined in claim 1, or a pharmaceutically acceptable salt or solvate thereof, to a patient in need thereof.

16. A pharmaceutical composition comprising (i) a therapeutically effective amount of a compound of formula Ia, as defined in claim 1, or a pharmaceutically acceptable salt or solvate thereof; and (ii) a pharmaceutically acceptable excipient.

17. The method according to claim 15, wherein the condition is a cardiovascular disorder.

18. The method according to claim 17, wherein the cardiovascular disorder is selected from the group consisting of hypertension, chronic heart failure and pulmonary arterial hypertension.

19. The method according to claim 15, wherein the condition is selected from the group consisting of cocaine addition, alcohol addition, adjunct opioid addiction, cognition decline in frontotemporal dementia, cognition decline in mild cognitive impairment, cognition decline in Alzheimer's disease, attention deficit-hyperactive disorder, post-traumatic stress disorder and unipolar depression.

Description

DETAILED DESCRIPTION OF THE EMBODIMENTS

A. Definitions

[0030] C.sub.1-C.sub.6 alkyl means a monovalent unsubstituted saturated straight-chain or branched-chain hydrocarbon radical having from 1 to 6 carbon atoms. C.sub.1-C.sub.2 alkyl, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.4 alkyl and C.sub.1-C.sub.5 alkyl have analogous meanings.

[0031] partially or fully deuterated C.sub.1-C.sub.6 alkyl means a C.sub.1-C.sub.6 alkyl wherein some or all of the hydrogen atoms, respectively, have been selectively replaced by deuterium.

[0032] C.sub.3-C.sub.6 cycloalkyl means a monovalent unsubstituted saturated cyclic hydrocarbon radical having from 3 to 6 carbon atoms. C.sub.5-C.sub.7 cycloalkyl has analogous meaning.

[0033] C.sub.2-C.sub.6 cyanoalkyl means a monovalent cyano-substituted saturated straight-chain or branched-chain hydrocarbon radical having from 2 to 6 carbon atoms including that which forms the cyano group.

[0034] C.sub.1-C.sub.6 mercaptoalkyl means a monovalent thiol-substituted saturated straight-chain or branched-chain hydrocarbon radical having from 1 to 6 carbon atoms.

[0035] halo means a fluorine (which may be depicted as F), chlorine (which may be depicted as Cl), bromine (which may be depicted as Br) or iodine (which may be depicted as I) radical.

[0036] amino means NH.sub.2.

[0037] Pharmaceutically acceptable salt means a salt such as those described in standard texts on salt formation, see for example: P. Stahl, et al., Handbook of Pharmaceutical Salts: Properties, Selection and Use (VCHA/Wiley-VCH, 2002), or S. M. Berge, et al., Pharmaceutical Salts (1977) Journal of Pharmaceutical Sciences, 66, 1-19.

[0038] Pharmaceutically acceptable solvate means a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, water or ethanol. The term hydrate may be employed when said solvent is water. Pharmaceutically acceptable solvates include hydrates and other solvates wherein the solvent of crystallization may be isotopically substituted, e.g. D.sub.2O, d.sub.6-acetone, d.sub.6-DMSO.

[0039] Pharmaceutically acceptable excipient means any ingredient of a pharmaceutical composition other than the compound(s) of the invention, or other known pharmacologically active components. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

[0040] Therapy, treatment and treating include both preventative and curative treatment of a condition, disease or disorder. It also includes slowing, interrupting, controlling or stopping the progression of a condition, disease or disorder. It also includes preventing, curing, slowing, interrupting, controlling or stopping the symptoms of a condition, disease or disorder.

[0041] Other variations to the disclosed embodiments can be understood and effected by those skilled in the art in practicing the claimed invention, from a study of the disclosure, and the appended claims. In the claims, the word comprising does not exclude other elements or steps, and the indefinite article a or an does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage.

B. Compounds

[0042] The invention provides a compound of formula Ia, as defined above, or a pharmaceutically acceptable salt or solvate thereof:

##STR00004##

[0043] B0. Core Structures

[0044] In some embodiments of formula Ia, n is 0 and a single bond joins the carbon atoms to which the CH.sub.2 moiety would be attached when n is 1 to form a structure of formula Ib

##STR00005##

[0045] In some embodiments of formula Ia, R.sub.4 and R.sub.5 combine, together with the carbon atom to which they are attached, to form a structure of formula Ic having a cyclopropyl ring wherein the CH.sub.2 moiety is optionally substituted with two deuterium atoms:

##STR00006##

[0046] In some embodiments more than 50%, preferably more than 90%, more preferably more than 95% and even more preferably more than 99% of substituents R.sub.5 and A of compounds of formula Ia have the stereochemical configuration of formula Id

##STR00007##

[0047] In some embodiments more than 50%, preferably more than 90%, more preferably more than 95% and even more preferably more than 99% of substituents R.sub.5 and A of compounds of formula Ia have the stereochemical configuration of formula Ie

##STR00008##

[0048] Preferred embodiments of formula Ia include compounds of formula Ih.

##STR00009##

[0049] In some particularly preferred embodiments of formula Ih more than 50%, preferably more than 90%, more preferably more than 95% and even more preferably more than 99% of substituents R.sub.5 and A of compounds of formula Ih have the stereochemical configuration of formula Iu

##STR00010##

[0050] In other particularly preferred embodiments of formula Ih more than 50%, preferably more than 90%, more preferably more than 95% and even more preferably more than 99% of substituents R.sub.5 and A of compounds of formula Ih have the stereochemical configuration of formula Iv

##STR00011##

[0051] Other preferred embodiments of formula Ia include compounds of formula Ik.

##STR00012##

[0052] In some particularly preferred embodiments of formula Ik more than 50%, preferably more than 90%, more preferably more than 95% and even more preferably more than 99% have the stereochemical configuration of formula In.

##STR00013##

[0053] B1. Substituent R.sub.1

[0054] R.sub.1 is selected from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl, partially or fully deuterated C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.2-C.sub.6 cyanoalkyl, C.sub.1-C.sub.6 mercaptoalkyl and amino.

[0055] R.sub.1 is preferably selected from the group consisting of hydrogen and C.sub.1-C.sub.6 alkyl. [0056] In some embodiments R.sub.1 is hydrogen. [0057] In some embodiments R.sub.1 is C.sub.1-C.sub.6 alkyl. [0058] In some embodiments R.sub.1 is partially deuterated C.sub.1-C.sub.6 alkyl. [0059] In some embodiments R.sub.1 is fully deuterated C.sub.1-C.sub.6 alkyl. [0060] In some embodiments R.sub.1 is C.sub.3-C.sub.6 cycloalkyl. [0061] In some embodiments R.sub.1 is C.sub.2-C.sub.6 cyanoalkyl. [0062] In some embodiments R.sub.1 is C.sub.1-C.sub.6 mercaptoalkyl. [0063] In some embodiments R.sub.1 is amino.

[0064] R.sub.1 is preferably selected from the group consisting of hydrogen, methyl, d3-methyl, propyl, cyclopropyl, cyanomethyl, mercaptoethyl and amino.

[0065] R.sub.1 is more preferably selected from the group consisting of hydrogen and methyl. [0066] In some embodiments R.sub.1 is preferably hydrogen. [0067] In some embodiments R.sub.1 is preferably methyl. [0068] In some embodiments R.sub.1 is preferably d3-methyl. [0069] In some embodiments R.sub.1 is preferably propyl. [0070] In some embodiments R.sub.1 is preferably cyclopropyl. [0071] In some embodiments R.sub.1 is preferably cyanomethyl. [0072] In some embodiments R.sub.1 is preferably mercaptoethyl. [0073] In some embodiments R.sub.1 is preferably amino.

[0074] R.sub.1 is most preferably hydrogen.

[0075] B2. Substituent R.sub.4 (when not combined with R.sub.5)

[0076] R.sub.4 is selected from the group consisting of hydrogen and C.sub.1-C.sub.3 alkyl. [0077] In some embodiments R.sub.4 is hydrogen. [0078] In some embodiments R.sub.4 is C.sub.1-C.sub.3 alkyl.

[0079] R.sub.4 is preferably selected from the group consisting of hydrogen and methyl. [0080] In some embodiments R.sub.4 is preferably hydrogen. [0081] In some embodiments R.sub.4 is preferably methyl.

[0082] R.sub.4 is most preferably hydrogen.

[0083] B3. Substituent R.sub.5 (when not combined with R.sub.4)

[0084] R.sub.5 is selected from the group consisting of hydrogen and C.sub.1-C.sub.2 alkyl. [0085] In some embodiments R.sub.5 is hydrogen. [0086] In some embodiments R.sub.5 is C.sub.1-C.sub.2 alkyl.

[0087] R.sub.5 is preferably selected from the group consisting of hydrogen and methyl. [0088] In some embodiments R.sub.5 is preferably hydrogen. [0089] In some embodiments R.sub.5 is preferably methyl.

[0090] R.sub.5 is most preferably hydrogen.

[0091] B4. Substituent R.sub.6

[0092] R.sub.6 is selected from the group consisting of C.sub.1-C.sub.6 alkyl, and partially or fully deuterated C.sub.1-C.sub.6 alkyl.

[0093] R.sub.6 is preferably C.sub.1-C.sub.6 alkyl. [0094] In some embodiments R.sub.6 is partially deuterated C.sub.1-C.sub.6 alkyl. [0095] In some embodiments R.sub.6 is fully deuterated C.sub.1-C.sub.6 alkyl.

[0096] R.sub.6 is preferably selected from the group consisting of methyl, n-butyl and d.sub.3-methyl. [0097] In some embodiments R.sub.6 is preferably methyl. [0098] In some embodiments R.sub.6 is preferably n-butyl. [0099] In some embodiments R.sub.6 is preferably d3-methyl.

[0100] R.sub.6 is most preferably methyl.

[0101] B5. Substituent A

[0102] A is selected from the group consisting of C.sub.5-C.sub.7 cycloalkyl, furanyl, thiophenyl, methylthiophenyl and

##STR00014##

[0103] wherein: [0104] X.sub.1 is hydrogen, halo or methyl; [0105] X.sub.1 is hydrogen or halo; [0106] X.sub.2 is hydrogen, halo or methyl; [0107] X.sub.2 is hydrogen or halo; and [0108] X.sub.3 is hydrogen or fluoro.

[0109] Preferably A is

##STR00015##

[0110] wherein X.sub.1, X.sub.1, X.sub.2, X.sub.2 and X.sub.3 are as defined above.

[0111] More preferably A is

##STR00016##

[0112] wherein: [0113] X.sub.1 is hydrogen, fluoro, chloro or methyl; [0114] X.sub.1 is hydrogen, fluoro or chloro; [0115] X.sub.2 is hydrogen, fluoro, chloro, bromo or methyl; [0116] X.sub.2 is hydrogen, fluoro, chloro or bromo; and [0117] X.sub.3 is hydrogen or fluoro. [0118] In one preferred embodiment not all of X.sub.1, X.sub.1, X.sub.2, X.sub.2 and X.sub.3 are hydrogen. Preferably A is selected from the group consisting of

##STR00017##

[0119] Most preferably A is selected from the group consisting of

##STR00018##

[0120] B6. Specific Embodiments of Compounds of Formula I

[0121] Various embodiments of substituents R.sub.1, R.sub.4, R.sub.5, R.sub.6, A, X, X.sub.1, X.sub.1, X.sub.2, X.sub.2 and X.sub.3 have been discussed in B1 to B5 above. These substituent embodiments can be combined with any of the core structure embodiments, discussed in B0 above, to form further embodiments of compounds of formula Ia. All embodiments of compounds of formula Ia formed by combining the substituent embodiments and core structure embodiments, discussed above, are within the scope of Applicants' invention, and some preferred further embodiments of the compounds of formula I are provided below.

[0122] In some embodiments of formula Ia, structures of formula Ih, Ik, and In (in particular formula Ih) are highly preferred

##STR00019##

wherein:

[0123] R.sub.1 is selected from the group consisting of hydrogen and methyl;

[0124] R.sub.4 (if present) is selected from the group consisting of hydrogen and methyl;

[0125] R.sub.5 (if present) is selected from the group consisting of hydrogen and methyl;

[0126] R.sub.6 is methyl; and

[0127] A is selected from the group consisting of

##STR00020##

[0128] In some embodiments of formula Ia, structures of formula Ir are even more highly preferred

##STR00021##

wherein:

[0129] A is selected from the group consisting of

##STR00022##

[0130] The following compounds represent specific embodiments of the invention:

(5aS,6aR)-5a-(2,5-difluorophenyl)-1-methyl-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione;
(5aS,6aR)-5a-(3,5-difluorophenyl)-1-methyl-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione;
(S)-1-butyl-6-(3,5-difluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione;
(S)-6-(3,5-difluorophenyl)-1-methyl-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione;
(R)-1-methyl-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione;
(S)-1-methyl-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione;
(S)-6-(2,6-difluorophenyl)-1-methyl-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione;
(5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-1-methyl-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione;
(5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-1-(methyl-d.sub.3)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione;
(R)-6-(3-chloro-2,6-difluorophenyl)-1-methyl-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione;
(S)-6-(3-chloro-2,6-difluorophenyl)-1-methyl-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione;
(5aS,6aR)-5a-(3-bromo-2,6-difluorophenyl)-1-methyl-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione;
(5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-methyl-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione;
(5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-1-methyl-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione;
(R)-6-(3-bromo-2,6-difluorophenyl)-1-methyl-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione;
(S)-6-(3-bromo-2,6-difluorophenyl)-1-methyl-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione;
(5aS,6aR)-5a-(3-chloro-5-fluorophenyl)-1-methyl-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione;
(5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-(methyl-d.sub.3)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione;
(S)-6-(5-bromo-2-fluorophenyl)-1-methyl-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione;
(R)-1-methyl-6-(2,3,6-trifluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione;
(R)-6-(5-bromo-2-fluorophenyl)-1-methyl-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione;
(R)-6-(2,6-difluorophenyl)-1-methyl-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione;
(R)-6-(5-chloro-2-fluorophenyl)-1-methyl-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione; and
(S)-6-(5-chloro-2-fluorophenyl)-1-methyl-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione.

C. Compositions

[0131] The compounds of the invention intended for pharmaceutical use may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients. Accordingly, the present invention is also directed to a pharmaceutical composition comprising (i) a therapeutically effective amount of a compound of formula Ia, as defined above, or a pharmaceutically acceptable salt or solvate thereof; and (ii) a pharmaceutically acceptable excipient.

[0132] Pharmaceutical compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).

D. Methods of Use

[0133] This invention is also directed to compounds of formula Ia, as defined above, or a pharmaceutically acceptable salt or solvate thereof, for use in therapy, in particular for the treatment of conditions ameliorated by inhibition of DH.

[0134] This invention is also directed to the use of compounds of formula Ia, as defined above, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treatment of conditions ameliorated by inhibition of DH.

[0135] This invention is also directed to a method for treating conditions ameliorated by inhibition of dopamine-beta-hydroxylase comprising administering a therapeutically effective amount of a compound of formula Ia, as defined above, or a pharmaceutically acceptable salt or solvate thereof, to a patient in need thereof.

[0136] Conditions ameliorated by inhibition of DH outside the CNS can include, but are not limited to: cardiovascular disorders such as hypertension, chronic heart failure and pulmonary arterial hypertension (PAH).

[0137] Conditions ameliorated by inhibition of DH within the CNS can include, but are not limited to: cocaine addiction, alcohol addiction, adjunct opioid addiction, cognition decline in FTD, cognition decline in MCI, cognition decline in AD, ADHD, PTSD and unipolar depression.

E. General Synthetic Methodology

[0138] The methods used for the synthesis of the compounds of the invention are illustrated by the schemes below. The starting materials and reagents used in preparing these compounds are available from commercial suppliers or can be prepared by methods obvious to those skilled in the art. To make the schemes easier to read, the option to incorporate deuterium at certain positions is not shown. Specifically, deuterated products can be produced using specifically deuterated starting materials, including, but not limited to, those used in the Examples below.

[0139] Compounds of formula Ia can generally be synthesised by the method outlined in Scheme 1:

##STR00023##

[0140] The starting material in Scheme 1 can generally be synthesised by the method outlined in Scheme 2:

##STR00024##

[0141] The starting material for Scheme 2, when n=0, can generally be synthesised by the method outlined in Scheme 3 as either enriched enantiomers or racemates:

##STR00025##

[0142] When R.sub.4 and R.sub.5 combine to form a cyclopropyl group, the starting material in Scheme 1 can generally be synthesised by the method outlined in Scheme 4:

##STR00026##

[0143] The starting material for Scheme 4 can generally be synthesised by the method outlined in Scheme 5:

##STR00027##

[0144] In turn, the starting material for Scheme 5 can generally be synthesised by the method outlined in Scheme 6 as either enriched enantiomers or racemates and including specific deuteration:

##STR00028##

[0145] In accordance with this synthetic methodology, the invention provides a process for the preparation of compounds of formula Ia

##STR00029##

which comprises reacting a compound of formula IIa wherein n, R.sub.4, R.sub.5, R.sub.6 and A are as defined for formula Ia above

##STR00030##

with a compound of formula R.sup.1NCS.

[0146] Compounds of formula IIa wherein n, R.sub.4, R.sub.5, R.sub.6 and A are as defined for formula Ia above are thus useful intermediates representing further embodiments of the present invention.

F. Examples

[0147] All compounds and intermediates were characterised by NMR. The spectra were recorded on a Bruker Avance III 600 MHz spectrometer with solvent used as internal standard. .sup.13C spectra were recorded at 150 MHz and .sup.1H spectra were recorded at 600 MHz. Data are reported in the following order: approximate chemical shift (ppm), number of protons, multiplicity (br, broad; d, doublet; m, multiplet; s, singlet; t, triplet) and coupling constant (Hz).

[0148] Room temperature in the following protocols means the temperature ranging from 20 C. to 25 C.

[0149] Preparative Example 1

Step 1: (E)-1,3-difluoro-5-(2-nitrovinyl)benzene

##STR00031##

To a solution of methanol (72 mL), water (36 mL), and 2.5 M sodium hydroxide (32.4 mL, 81 mmol) was added a solution of 3,5-difluorobenzaldehyde (10 g, 70.4 mmol) and nitromethane (4.36 mL, 81 mmol) in methanol (12.00 mL) dropwise over 30 min at 5 C., while the internal temperature was maintained between 5 and 10 C. with external cooling. The reaction was then agitated in the cold for an additional 0.5 h, and then a solution of cc. HCl (11.73 mL, 141 mmol) in water (36 mL) was added in one portion at 0-10 C. with stirring. The resulting crystals were collected, washed with water and dried to give the product as a light yellow powder. (Yield: 7.0 g, 54%).
Step 2: (R)-diethyl2-(1-(3,5-difluorophenyl)-2-nitroethyl)malonate

##STR00032##

To a stirred solution of (E)-1,3-difluoro-5-(2-nitrovinyl)benzene (7.4 g, 40.0 mmol) in dry tetrahydrofuran (75 mL) was added 4-((S)-hydroxy((1S,2R,4S,5R)-5-vinylquinuclidin-2-yl)methyl)quinolin-6-ol (CAS #70877-75-7) (0.620 g, 1.999 mmol) at room temperature with stirring followed by addition of diethyl malonate (8.65 mL, 56.7 mmol). The mixture was cooled to 5 to 7 C. under inert atmosphere and stirred for 20 h in the cold. Thereupon, the mixture was evaporated to dryness under vacuum and the residue was taken up in dichloromethane (100 mL), washed with 1 M HCl, brine, dried over MgSO.sub.4 and filtered on a silica pad. The filtrate was concentrated to 20 mL, and the residue was crystallized on dilution with petroleum ether (ca. 50 mL). The mixture was further diluted with petroleum ether (120 mL), and aged at 5-10 C. The resulting solid was collected, washed with petroleum ether, and dried to give the product as an off-white powder. (Yield: 9.1 g, 70%).
Step 3: (4R)-ethyl 4-(3,5-difluorophenyl)-2-oxopyrrolidine-3-carboxylate

##STR00033##

To a suspension of (R)-diethyl 2-(1-(3,5-difluorophenyl)-2-nitroethyl)malonate (9 g, 26.1 mmol) in methanol (150 mL) was added nickel(II) chloride hexahydrate (6.20 g, 26.1 mmol) followed by addition of sodium borohydride (7.89 g, 209 mmol) in portions with ice cooling. The mixture was stirred for 6 h at room temperature, then quenched with ammonium chloride solution (250 mL), diluted with dichloromethane (150 mL), acidified with 6 M HCl to pH=2, and stirred for 16 h. Thereupon, the mixture was extracted with dichloromethane, the organic phase was dried over MgSO.sub.4 and evaporated to dryness to give the product as a beige powder. (Yield: 6.87 g, 98%).
Step 4: (4R)-4-(3,5-difluorophenyl)-2-oxopyrrolidine-3-carboxylic acid

##STR00034##

To a stirred solution of (4R)-ethyl 4-(3,5-difluorophenyl)-2-oxopyrrolidine-3-carboxylate (6.85 g, 25.4 mmol) in ethanol (100 mL) was added 1 M sodium hydroxide (30.5 mL, 30.5 mmol). The resulting suspension was stirred for 1 h, the organics were then removed under vacuum, and the residue was dissolved in water (250 mL). The product was crystallized on acidification with 6 M HCl. The resulting crystals were collected, washed with cold water and dried under vacuum at 50 C. to give the product as a beige powder Yield: 5.2 g, 21, 85%.
Step 5: (R)-4-(3,5-difluorophenyl)pyrrolidin-2-one

##STR00035##

A solution of (4R)-4-(3,5-difluorophenyl)-2-oxopyrrolidine-3-carboxylic acid (5.2 g, 21.56 mmol) in toluene (300 mL) was stirred under reflux for 3 h, whereupon the mixture was evaporated to dryness, Crystallization from petroleum ether afforded beige powder. Yield: 4.06 g, 96%.
Step 6: (R)-tert-butyl 4-(3,5-difluorophenyl)-2-oxopyrrolidine-1-carboxylate

##STR00036##

To a stirred solution of (R)-4-(3,5-difluorophenyl)pyrrolidin-2-one (4.05 g, 20.54 mmol) in dry dichloromethane (15 mL) was added at room temperature di-tert-butyl dicarbonate (6.72 g, 30.8 mmol) followed by addition of N,N-dimethylpyridin-4-amine (2.509 g, 20.54 mmol) and triethyl amine (2.86 mL, 20.54 mmol). The mixture was then stirred at room temperature for 3 h, and then concentrated under vacuum. Chromatography (petroleum etherethyl acetate; 4:1) gave an oil which was crystallized from petroleum ether (60 mL), The product was isolated as a white powder. Yield: 6.24 g, 88%.
Step 7: (4R)-tert-butyl 4-(3,5-difluorophenyl)-2-hydroxypyrrolidine-1-carboxylate

##STR00037##

To a stirred solution of (R)-tert-butyl 4-(3,5-difluorophenyl)-2-oxopyrrolidine-1-carboxylate (2 g, 6.73 mmol) in dry diethyl ether (30 mL) was added dropwise 65% RED-Al (bis(2-methoxyethoxy)aluminum(III) sodium hydride) (1.212 mL, 4.04 mmol) in toluene at 0-5 C. under nitrogen and the mixture was stirred for 30 min. in the cold. Thereupon, the mixture was quenched with sodium bicarbonate solution and stirred for 30 min. The organic phase was dried over MgSO.sub.4, and evaporated to dryness to give the product as colourless oil. (Yield: 2.07 g, 93%).
Step 8: (4R)-tert-butyl 2-cyano-4-(3,5-difluorophenyl)pyrrolidine-1-carboxylate

##STR00038##

To a stirred solution of (4R)-tert-butyl 4-(3,5-difluorophenyl)-2-hydroxypyrrolidine-1-carboxylate (2 g, 6.68 mmol) in dry dichloromethane (50 mL) was added trimethylsilanecarbonitrile (1.792 mL, 13.36 mmol) followed by addition of boron trifluoride etharate (1.863 mL, 14.70 mmol) at 70 C. The mixture was stirred for 4 h in the cold, quenched with sodium bicarbonate solution, and then allowed to warm up with stirring to room temperature. The organic phase was dried over MgSO.sub.4, filtered and evaporated to dryness under vacuum. Chromatography (petroleum etherethyl acetate; 9:1) afforded the compound as a colourless oil. (Yield: 1.36 g, 66%).
Step 9: (4R)-1-(tert-butoxycarbonyl)-4-(3,5-difluorophenyl)pyrrolidine-2-carboxylic acid

##STR00039##

To a stirred solution of (4R)-tert-butyl 2-cyano-4-(3,5-difluorophenyl)pyrrolidine-1-carboxylate (1.35 g, 4.38 mmol) in ethanol (15 mL) was added 3 M sodium hydroxide (7.30 mL, 21.89 mmol) and the solution was gently refluxed (oil bath at 80 C.) for 3 h. Thereupon, ethanol was removed under vacuum and the residue was diluted with water (10 mL), and then acidified with 2 M HCl to pH=2 at 10-15 C. The mixture was extracted with dichloromethane (40 mL), the insoluble materials in both phases was filtered off, whereupon the organic phase was washed with brine, dried over MgSO.sub.4 and evaporated to dryness to give 0.89 g of yellowish oil. (Yield: 62%).
Example 1: (5aS,6aR)-5a-(2,5-difluorophenyl)-1-methyl-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione

##STR00040##

Compound was prepared in an analogous manner to Example 3 from (5S)-3-(tert-butoxycarbonyl)-5-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid and methylmagnesium iodide and isolated as a yellow solid.

.SUP.1.H NMR (DMSO-d6): 11.66 (1H, br s), 7.28 (2H, m), 7.20 (1H, m), 4.06 (1H, d, J=12.0 Hz), 3.78 (1H, d, J=12.0 Hz), 2.86 (1H, dd, J=8.2, 4.3 Hz), 2.09 (1H, m), 2.04 (3H, s), 1.63 (1H, dd, J=8.1, 5.4 Hz), 1.13 (1H, t, J=4.8 Hz).

.SUP.13.C NMR (DMSO-d6): 158.8, 158.7, 157.2, 157.1, 155.7, 130.3, 128.8, 128.8, 128.8, 128.7, 128.6, 117.2, 117.1, 117.0, 116.9, 116.8, 115.9, 115.8, 115.7, 115.7, 114.8, 51.5, 32.5, 22.4, 20.3, 9.4.

[0150] Example 2: (5aS,6aR)-5a-(3,5-difluorophenyl)-1-methyl-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione

##STR00041##

Compound was prepared in an analogous manner to Example 3 from (5S)-3-(tert-butoxycarbonyl)-5-(3,5-difluorophenyl)-3-azabicyclo [3.1.0]hexane-2-carboxylic acid and methylmagnesium iodide and isolated as a yellow solid.

.SUP.1.H NMR (DMSO-d6): 1.63 (1H, br s), 7.10 (3H, m), 4.17 (1H, d, J=12.0 Hz), 4.00 (1H, d, J=12.2 Hz), 2.97 (1H, dd, J=8.3, 4.3 Hz), 2.03 (3H, s), 1.65 (1H, dd, J=8.2, 5.1 Hz), 1.15 (1H, m).

.SUP.13.C NMR (DMSO-d6): 163.4, 163.3, 161.8, 161.7, 156, 145, 130.2, 114.5, 110, 110, 109.9, 109.9, 102.1, 50.7, 36.1, 25.4, 22.4, 9.4.

[0151] Example 3: (S)-1-butyl-6-(3,5-difluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione
Step 1: (4S)-tert-butyl 4-(3,5-difluorophenyl)-2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate

##STR00042##

To a solution of (4S)-1-(tert-butoxycarbonyl)-4-(3,5-difluorophenyl)pyrrolidine-2-carboxylic acid (prepared in a manner analogous to Preparative Example 1, step 9) (0.982 g, 3 mmol) in dry dichloromethane (10 mL) was added di(1H-imidazol-1-yl)methanone (0.584 g, 3.60 mmol) in portions at room temperature and the mixture was stirred for 30 min. Thereupon, N,O-dimethylhydroxylamine hydrochloride (0.351 g, 3.60 mmol) was added and the stirring was continued at room temperature for 40 h. The reaction was then washed with water, the organic phase was dried over MgSO.sub.4 and concentrated under vacuum. Chromatography (petroleum etherethyl acetate; 2:1) afforded the product as an off-white solid. (Yield: 0.92 g, 83%).
Step 2: tert-butyl (4S)-4-(3,5-difluorophenyl)-2-pentanoylpyrrolidine-1-carboxylate

##STR00043##

To a solution of (4S)-tert-butyl 4-(3,5-difluorophenyl)-2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (0.40 g, 1.08 mmol) in dry tetrahydrofuran (2 mL) was added 2 M butylmagnesium bromide (1.62 mL, 3.24 mmol) at 0-5 C. under nitrogen. The mixture was allowed to warm up to room temperature and stirred for 3 h. Thereupon, the mixture was poured onto 1 M HCl and then extracted with diethyl ether. The organic phase was washed with brine, dried over MgSO.sub.4, and evaporated to dryness. Chromatography (petroleum etherethyl acetate; 9:1) afforded the product as a colourless oil. (Yield: 0.2 g, 50%).
Step 3: (S)-1-benzyl-6-(3,5-difluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione

##STR00044##

A mixture of (4S)-tert-butyl 4-(3,5-difluorophenyl)-2-pentanoylpyrrolidine-1-carboxylate (0.19 g, 0.517 mmol) and 4 M HCl (2.59 mL, 10.34 mmol) in dioxane was stirred at room temperature overnight. The mixture was then cooled to room temperature and evaporated to dryness. The thus obtained oily residue was dissolved in a mixture of ethanol (2 mL) and water (2 mL), followed by addition of potassium thiocyanate (0.055 g, 0.569 mmol) and 6 M HCl (0.043 mL, 0.259 mmol). The mixture was stirred under reflux for 1 h, then stirred at room temperature for 30 min. The obtained solid was collected by filtration, washed with a mixture of ethanol water (1:1) and dried under vacuum at 50 C. to give the product as a light beige powder. (Yield: 0.12 g, 75%).
.sup.1H NMR (DMSO-d6): 11.71 (1H, s), 7.13 (3H, m), 4.14 (1H, dd, J=11.2, 7.9 Hz), 4.07 (1H, quin, J=8.1 Hz), 3.67 (1H, dd, J=11.1, 8.3 Hz), 3.20 (1H, dd, J=15.0, 7.8 Hz), 2.84 (1H, dd, J=15.1, 8.8 Hz), 2.35 (2H, t, J=7.5 Hz), 1.50 (2H, m), 1.26 (2H, m), 0.86 (3H, t, J=7.4 Hz).

.SUP.13.C NMR (DMSO-d6): 163.3, 163.2, 161.7, 161.6, 155.1, 145.8, 145.7, 145.6, 127.6, 120, 110.8, 110.7, 110.6, 110.6, 102.6, 102.5, 102.3, 49.9, 46.5, 30.4, 29.8, 23.6, 21.5, 13.6.

[0152] Example 4: (S)-6-(3,5-difluorophenyl)-1-methyl-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione
Step 1: ((4S)-tert-butyl 2-(cyano(hydroxy)methyl)-4-(3,5-difluorophenyl)pyrrolidine-1-carboxylate

##STR00045##

To a stirred solution of (4S)-tert-butyl 4-(3,5-difluorophenyl)-2-formylpyrrolidine-1-carboxylate (1.2 g, 3.85 mmol) in a mixture of tetrahydrofuran (10 mL) and water (5 mL) was added potassium cyanide (0.301 g, 4.63 mmol) followed by addition of cc HCl (0.319 mL, 3.85 mmol). The mixture was stirred for 8 h, then extracted with dichloromethane. The organic phase was washed with brine, dried over MgSO.sub.4 and evaporated to dryness to give (4S)-tert-butyl 2-(cyano(hydroxy)methyl)-4-(3,5-difluorophenyl)pyrrolidine-1-carboxylate as a yellowish oil. (Yield: 1.44 g, 99%).
Step 2: (4S)-tert-butyl 4-(3,5-difluorophenyl)-2-(2-ethoxy-1-hydroxy-2-oxoethyl)pyrrolidine-1-carboxylate

##STR00046##

A mixture of (4S)-tert-butyl 2-(cyano(hydroxy)methyl)-4-(3,5 -difluorophenyl)pyrrolidine-1-carboxylate (1.43 g, 3.80 mmol) and 2 M HCl (28.5 mL, 57.1 mmol) was stirred under reflux for 16 h. After cooling to room temperature the mixture was filtered through a celite plug to remove insoluble coloured precipitate and then the filtrate was evaporated to dryness under vacuum. The residue was azeotroped twice with dry ethanol and the residue was taken up in abs. ethanol (20 mL). The thus obtained solution was treated with 4 M HCl (9.51 mL, 38.0 mmol) in dioxane and stirred under reflux for 2 h. The mixture was evaporated to dryness, and then azeotroped with abs. ethanol. The resulting semi-solid was taken up in abs. ethanol (30 mL), neutralized by addition of triethylamine to pH=6-7, then a second crop of triethylamine (0.530 mL, 3.80 mmol) was added followed by addition of di-tert-butyl dicarbonate (0.830 g, 3.80 mmol). The reaction was allowed to stir at room temperature for 2 h, and then evaporated to dryness at 40 C. The residue was partitioned between dichloromethane and water, the organic phase was dried over MgSO.sub.4 and concentrated under reduced pressure. Chromatography (petroleum etherethyl acetate; 9:1, then 4:1) gave the product as a yellow oil. (Yield: 1.16 g, 79%).
Step 3: (4S)-tert-butyl 4-(3,5-difluorophenyl)-2-(2-ethoxy-2-oxoacetyl)pyrrolidine-1-carboxylate

##STR00047##

To a stirred solution of (4S)-tert-butyl 4-(3,5-difluorophenyl)-2-(2-ethoxy-1-hydroxy-2-oxoethyl)pyrrolidine-1-carboxylate (1.15 g, 2.98 mmol) in dry dichloromethane (25 mL) was added Dess-Martin periodinane (3-oxo-1.sup.5-benzo[d][1,2]iodaoxole-1,1,1(3H)-triyl triacetate) (1.266 g, 2.98 mmol) at room temperature in one portion and the mixture was stirred for 2 h. The reaction mixture was concentrated under vacuum, whereupon the residue was purified by chromatography (petroleum etherethyl acetate; 4:1). The product was isolated as a yellowish oil. (1.08 g, 94% yield).
Step 4: ethyl 2-((4S)-4-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-oxoacetate hydrochloride

##STR00048##

To a stirred solution of (4S)-tert-butyl 4-(3,5-difluorophenyl)-2-(2-ethoxy-2-oxoacetyl)pyrrolidine-1-carboxylate (0.4 g, 1.043 mmol) in 4 M HCl (5.22 mL, 20.87 mmol) in dioxane was stirred at room temperature for 4 h. The reaction mixture was diluted with a mixture of diethyl ether (20 mL) and petroleum ether (5 mL) and stirred for 30 min, Thereupon, the resulting precipitate was collected, washed with diethyl ether, petroleum ether and dried under vacuum at 50 C. to give ethyl 2-((4S)-4-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-oxoacetate hydrochloride as a white powder. (Yield: 0.34 g, 92%).
Step 5: (S)-ethyl 6-(3,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazole-1-carboxylate

##STR00049##

A solution of ethyl 2-((4S)-4-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-oxoacetate hydrochloride (0.33 g, 1.032 mmol), 6 M HCl (0.086 mL, 0.516 mmol) and potassium thiocyanate (0.110 g, 1.135 mmol) in a mixture of ethanol (5 mL) and water (5 mL) was stirred under reflux for 30 min. The reaction was then cooled to room temperature, and the resulting solid was collected, washed with a mixture of ethanol and water (1:1), and dried under vacuum at 50 C. to give (S)-ethyl 6-(3,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazole-1-carboxylate as a white solid. (Yield: 0.28 g, 84%).
Step 6: S)-6-(3,5-difluorophenyl)-1-methyl-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione

##STR00050##

To a solution of (S)-ethyl 6-(3,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imidazole-1-carboxylate (0.1 g, 0.308 mmol) in dry tetrahydrofuran (2 mL) was added sodium borohydride (0.058 g, 1.542 mmol) followed by addition of boron trifluoride etherate (0.195 mL, 1.542 mmol) with ice-water bath cooling. The mixture was allowed to warm up to room temperature and stirred for 16 h. Thereupon, the mixture was cooled again to 0-5 C., and quenched with 2 M HCl (1.233 ml, 2.467 mmol). The organic solvents were removed under vacuum, and then the residue extracted with ethyl acetate. The organic phase was dried over MgSO.sub.4, filtered and evaporated to dryness. Chromatography (petroleum etherethyl acetate; 1:1 gave (S)-6-(3,5-difluorophenyl)-1-methyl-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione as a white powder (0.021 g, 0.079 mmol, 25.6% yield).
.sup.1H NMR (DMSO-d6): 11.69 (1H, br s), 7.13 (3H, m), 5.76 (1H, s), 4.15 (1H, dd, J=11.2, 7.9 Hz), 4.07 (1H, quin, J=7.8 Hz), 3.66 (1H, dd, J=11.2, 8.4 Hz), 3.18 (1H, m), 2.82 (1H, ddd, J=15.0, 8.9, 1.3 Hz), 1.98 (3H, s).

.SUP.13.C NMR (DMSO-d6): 163.3, 163.2, 161.7, 161.6, 155.1, 145.7, 145.7, 145.6, 127.8, 115.4, 110.8, 110.7, 110.6, 110.6, 102.6, 102.5, 102.3, 50.0, 46.5, 30.0, 9.4.

[0153] Example 5: (R)-1-methyl-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]-imidazole-3-thione

##STR00051##

Compound was prepared in an analogous manner to Example 3 from (4R)-1-(tert-butoxycarbonyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-2-carboxylic acid and methylmagnesium iodide and isolated as an off-white powder.
.sup.1H NMR (DMSO-d6): 11.74 (1H, br s), 7.85 (1H, m), 4.49 (1H, quin, J=8.5 Hz), 4.42 (1H, m), 4.15 (1H, dd, J=11.6, 9.2 Hz), 3.76 (1H, dd, J=11.7, 7.8 Hz), 3.27 (1H, dd, J=15.6, 9.2 Hz), 2.89 (1H, dd, J=15.4, 7.9 Hz), 1.97 (3H, s).

.SUP.13.C NMR (DMSO-d6): 155.0, 146.4, 146.3, 146.3, 145.3, 145.2, 144.8, 144.7, 144.6, 143.7, 143.6, 127.5, 120.5, 120.4, 120.3, 115.3, 105.9, 105.7, 105.6, 48.4, 35.9, 28.6, 9.3.

[0154] Example 6: (S)-1-methyl-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

##STR00052##

Compound was prepared in an analogous manner to Example 3 from (4S)-1-(tert-butoxycarbonyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-2-carboxylic acid and methylmagnesium iodide and isolated as a light beige powder.
.sup.1H NMR (DMSO-d6): 11.74 (1H, br s), 7.85 (1H, m), 4.49 (1H, quin, J=8.5 Hz), 4.15 (1H, dd, J=11.6, 9.2 Hz), 3.76 (1H, dd, J=11.7, 7.8 Hz), 3.27 (1H, dd, J=15.6, 9.2 Hz), 2.89 (1H, dd, J=15.4, 7.9 Hz), 1.97 (3H, s).

.SUP.13.C NMR (DMSO-d6): 155, 146.4, 146.3, 146.3, 145.3, 145.2, 144.8, 144.7, 144.6, 143.7, 143.6, 127.5, 120.5, 120.4, 120.3, 115.3, 105.9, 105.7, 105.6, 48.7, 48.4, 35.9, 28.6, 9.3.

[0155] Example 7: (S)-6-(2,6-difluorophenyl)-1-methyl-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

##STR00053##

Compound was prepared in an analogous manner to Example 3 from (4S)-1-(tert-butoxycarbonyl)-4-(2,6-difluorophenyl)pyrrolidine-2-carboxylic acid and methylmagnesium iodide and isolated as a light beige powder.
.sup.1H NMR (DMSO-d6): 11.72 (1H, br s), 7.40 (1H, m), 7.13 (2H, m), 4.41 (1H, quin, J=8.7 Hz), 4.12 (1H, br t, J=10.1 Hz), 3.70 (1H, dd, J=8.8, 10.8 Hz), 3.21 (1H, br dd, J=15.3, 9.2 Hz), 2.84 (1H, br dd, J=15.2, 8.6 Hz), 1.97 (3H, s).

.SUP.13.C NMR (DMSO-d6): 161.6, 161.6, 160.0, 159.9, 155.0, 129.8, 129.7, 129.7, 127.8, 116.6, 116.5, 116.4, 115.2, 112.3, 112.2, 112.1, 112.1, 48.6, 35.4, 28.8, 9.3.

[0156] Example 8: (5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-1-methyl-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione

##STR00054##

Compound was prepared in an analogous manner to Example 3 from tert-butyl (1S,5R)-1-(5-chloro-2-fluorophenyl)-4-(methoxy(methyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate and methylmagnesium iodide. The product was isolated as a beige solid.
.sup.1H NMR (DMSO-d6): 11.65 (1H, br s), 7.47 (1H, dd, J=6.5, 2.6 Hz), 7.42 (1H, ddd, J=8.8, 4.4, 2.7 Hz), 7.29 (1H, dd, J=10.0, 8.9 Hz), 4.06 (1H, d, J=11.7 Hz), 3.77 (1H, d, J=12.0 Hz), 2.87 (1H, dd, J=8.2, 4.3 Hz), 2.04 (3H, m), 1.64 (1H, dd, J=8.1, 5.4 Hz), 1.12 (1H, t, J=4.8 Hz).

.SUP.13.C NMR (DMSO-d6): 161.3, 159.7, 155.7, 130.3, 130.1, 130.1, 129.3, 129.3, 129.0, 128.9, 128.3, 128.3, 117.6, 117.4, 114.8, 51.5, 51.5, 32.3, 22.3, 20.2, 9.4.

[0157] Example 9: (5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-1-(methyl-d.sub.3)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione

##STR00055##

Compound was prepared in an analogous manner to Example 3 from tert-butyl (1S,5R)-1-(5-chloro-2-fluorophenyl)-4-(methoxy(methyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate and methyl-d.sub.3-magnesium iodide. The product was isolated as a light orange solid.
.sup.1H NMR (DMSO-d6): 11.65 (1H, s), 7.47 (1H, dd, J=6.6, 2.8 Hz), 7.42 (1H, ddd, J=8.8, 4.4, 2.7 Hz), 7.29 (1H, m), 4.06 (1H, d, J=11.9 Hz), 3.77 (1H, d, J=12.0 Hz), 2.87 (1H, dd, J=8.3, 4.3 Hz), 1.64 (1H, dd, J=8.3, 5.4 Hz), 1.12 (1H, t, J=4.8 Hz).

.SUP.13.C NMR (DMSO-d6): 161.3, 159.7, 155.7, 155.6, 130.3, 130.1, 130.1, 129.3, 129.3, 129.0, 128.9, 128.3, 128.3, 117.6, 117.4, 114.7, 114.6, 51.5, 51.5, 32.3, 22.3, 20.2.

[0158] Example 10: (R)-6-(3-chloro-2,6-difluorophenyl)-1-methyl-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

##STR00056##

Compound was prepared in an analogous manner to Example 3 from (4S)-1-(tert-butoxycarbonyl)-4-(3-chloro-2,6-difluorophenyl)pyrrolidine-2-carboxylic acid and methylmagnesium iodide and isolated as an off-white powder.
.sup.1H NMR (DMSO-d6): 11.73 (1H, br s), 7.61 (1H, td, J=8.8, 5.6 Hz), 7.21 (1H, t, J=9.5 Hz), 4.44 (1H, quin, J=8.6 Hz), 4.13 (1H, dd, J=11.4, 9.2 Hz), 3.72 (1H, dd, J=11.6, 7.9 Hz), 3.23 (1H, m), 2.84 (1H, dd, J=15.5, 8.1 Hz), 1.97 (3H, s).

.SUP.13.C NMR (DMSO-d6): 160.2, 160.1, 158.5, 158.5, 156.6, 156.5, 155, 154.9, 154.9, 129.7, 129.7, 127.7, 118.9, 118.7, 118.6, 116.1, 116.1, 116.0, 116.0, 115.2, 113.3, 113.3, 113.1, 113.1, 48.5, 35.8, 28.7, 9.4.

[0159] Example 11: (S)-6-(3-chloro-2,6-difluorophenyl)-1-methyl-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

##STR00057##

Compound was prepared in an analogous manner to Example 3 from (4R)-1-(tert-butoxycarbonyl)-4-(3-chloro-2,6-difluorophenyl)pyrrolidine-2-carboxylic acid and methylmagnesium iodide and isolated as a light beige powder.
.sup.1H NMR (DMSO-d6): 11.73 (1H, br s), 7.61 (1H, td, J=8.8, 5.6 Hz), 7.21 (1H, t, J=9.5 Hz), 4.44 (1H, quin, J=8.6 Hz), 4.13 (1H, dd, J=11.4, 9.2 Hz), 3.72 (1H, dd, J=11.6, 7.9 Hz), 3.23 (1H, m), 2.84 (1H, dd, J=15.5, 8.1 Hz), 1.97 (3H, s).

.SUP.13.C NMR (DMSO-d6): 160.2, 160.1, 158.5, 158.5, 156.6, 156.5, 154.9, 154.9, 129.7, 129.6, 127.7, 118.9, 118.7, 118.6, 116.1, 116.1, 116.0, 115.9, 115.2, 113.3, 113.3, 113.1, 113.1, 48.5, 35.7, 28.7, 9.4.

[0160] Example 12: (5aS,6aR)-5a-(3-bromo-2,6-difluorophenyl)-1-methyl-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione

##STR00058##

Compound was prepared in an analogous manner to Example 3 from 2-(5-bromo-2,6-difluorophenyl)acetonitrile and (R)-2-(chloromethyl)oxirane and isolated as a white solid.

.SUP.1.H NMR (DMSO-d6): 11.68 (1H, br s), 7.74 (1H, td, J=8.4, 5.9 Hz), 7.15 (1H, td, J=9.2, 1.2 Hz), 4.01 (1H, d, J=12.3 Hz), 3.71 (1H, d, J=12.0 Hz), 2.72 (1H, dd, J=8.3, 4.5 Hz), 2.05 (3H, s), 1.65 (1H, dd, J=8.2, 5.6 Hz), 1.25 (1H, t, J=5.0 Hz).

.SUP.13.C NMR(DMSO-d6): 161.9, 161.9, 160.3, 160.2, 158.8, 158.8, 157.2, 157.1, 155.7, 133.0, 133.0, 130.0, 117.2, 117.1, 115.1, 113.5, 113.3, 103.7, 103.7, 103.6, 51.4, 26.5, 21.8, 20.9, 9.4.

[0161] Example 13: (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-methyl-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione

##STR00059##

Step 1: ((1R,2S)-2-(aminomethyl)-2-(5-bromo-2-fluorophenyl)cyclopropyl)methanol

##STR00060##

To a stirred solution of 2-(5-bromo-2-fluorophenyl)acetonitrile (10 g, 46.7 mmol) in dry tetrahydrofuran (100 mL), was added (R)-2-(chloromethyl)oxirane (4.38 mL, 56.1 mmol) at room temperature, under inert atmosphere. The reaction was then cooled to 0 C. and 2 M sodium bis(trimethylsilyl)amide in tetrahydrofuran (40.9 mL, 82 mmol) was added dropwise keeping the temperature between 0-5 C. Thereupon, the obtained red mixture was allowed to warm up to room temperature and stirred for 3 h. The reaction was diluted with dry tetrahydrofuran (100 mL), cooled to 0 C. and sodium borohydride (7.07 g, 187 mmol) was added, followed by dropwise addition of boron trifluoride diethyl etherate (23.68 mL, 187 mmol). The mixture was allowed to warm to room temperature naturally and stirred overnight. The obtained pale yellow suspension was then cooled to 0 C. and carefully quenched with 2 M HCl (140 ml, 280 mmol). The tetrahydrofuran was evaporated off under vacuum, the aqueous phase was washed with diethyl ether (discarded), then was basified to pH=10 (3 M NaOH) and extracted with dichloromethane. The organic phase was dried over MgSO.sub.4, filtered and evaporated to leave a yellow oil. Yield: 11.75 g, 73%.
Step 2: tert-butyl (((1S,2R)-1-(5-bromo-2-fluorophenyl)-2-(hydroxymethyl)cyclopropyl)methyl)carbamate

##STR00061##

To an ice-cooled solution of ((1R,2S)-2-(aminomethyl)-2-(5-bromo-2-fluorophenyl)cyclopropyl)methanol (11.75 g, 42.9 mmol) in ethanol (145 mL), was added di-tert-butyl dicarbonate (9.35 g, 42.9 mmol). The solution was stirred at room temperature for 4 h. Then the solvent was evaporated and the residue was separated on a column. The titled compound was isolated as a yellow foam. Yield: 10.1 g, 56%.
Step 3: tert-butyl (1S,5R)-1-(5-bromo-2-fluorophenyl)-4-hydroxy-3-azabicyclo[3.1.0]hexane-3-carboxylate

##STR00062##

To a stirred solution of oxalyl dichloride (2.60 mL, 29.7 mmol) in dry dichloromethane (62.8 mL), was added dropwise a solution of DMSO (4.21 mL, 59.4 mmol) in dry dichloromethane (12.5 mL) at 78 C. over 30 min. The reaction mixture was stirred for 5 min in the cold, and then a solution of tert-butyl (((1S,2R)-1-(5-bromo-2-fluorophenyl)-2-(hydroxymethyl)cyclopropyl)methyl)carbamate (10.1 g, 27.0 mmol) in dry dichloromethane (25 mL) was added, dropwise over 30 min. The mixture was stirred at 78 C. for 1 h, and then triethylamine (18.8 mL, 135 mmol) was added. The reaction was allowed to warm up gradually to room temperature and stirred for 2 h. Thereupon the mixture was washed three times with water, dried over MgSO.sub.4, filtered and evaporated to give a yellow oil. Yield: 10.1 g, 85%.
Step 4: tert-butyl (1S,5R)-1-(5-bromo-2-fluorophenyl)-4-cyano-3-azabicyclo[3.1.0]hexane-3-carboxylate

##STR00063##

To a stirred solution of tert-butyl (1S,5R)-1-(5-bromo-2-fluorophenyl)-4-hydroxy-3-azabicyclo[3.1.0]hexane-3-carboxylate (10.1 g, 27.1 mmol) in dry dichloromethane (133 mL) was added trimethylsilanecarbonitrile (9.71 mL, 72.4 mmol) at room temperature under inert atmosphere. Then, the solution was cooled to 78 C. and boron trifluoride diethyl etherate (10.08 mL, 80.0 mmol) was added dropwise. The reaction mixture was stirred at 78 C. for 4 h., and then saturated solution of NaHCO.sub.3 was added and the mixture was allowed to warm to room temperature. The organic phase was separated and aqueous phase was extracted with dichloromethane. The combined organic phases were dried over MgSO.sub.4, filtered and evaporated to give 10.3 g of yellow oil. Yield: 85%.
Step 5: (1R,5S)-5-(5-bromo-2-fluorophenyl)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid

##STR00064##

To a stirred solution of tert-butyl (1S,5R)-1-(5-bromo-2-fluorophenyl)-4-cyano-3-azabicyclo[3.1.0]hexane-3-carboxylate (10.3 g, 27.0 mmol) in ethanol (93 mL), at room temperature was added a solution of 3 M NaOH (45 mL, 135 mmol). The solution was heated at 80 C. for 3 h. Then, the reaction was cooled to room temperature, ethanol was evaporated and the aq. phase was acidified with 2N HCl solution, the resulting solid was filtered off, dissolved in a mixture of dichloromethaneisopropanol (7:3). The organic phase was dried over MgSO.sub.4, filtered and evaporated to give the titled product as a yellow semi-solid. Yield: 10.5 g, 78%.
Step 6: tert-butyl (1S,5R)-1-(5-bromo-2-fluorophenyl)-4-(methoxy(methyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

##STR00065##

To a stirred solution of ((1R,5S)-5-(5-bromo-2-fluorophenyl)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (2.5 g, 6.25 mmol) in anhydrous dichloromethane (36 mL) was added di(1H-imidazol-1-yl)methanone (1.215 g, 7.50 mmol) portion wise under nitrogen and the reaction stirred for 30 min. Thereupon, N,O-dimethylhydroxylamine hydrochloride (0.731 g, 7.50 mmol) was added and the mixture was stirred overnight. The reaction mixture was then diluted with dichloromethane (ca. to 60 mL) and washed with water. The organic phase was dried over MgSO4, filtered and evaporated to give the titled product as a yellow yellow oil. Yield: 1.57 g, 45%.
Step 7: tert-butyl (1S,5R)-4-acetyl-1-(5-bromo-2-fluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

##STR00066##

To a stirred solution of (1S,5R)-tert-butyl 1-(5-bromo-2-fluorophenyl)-4-(methoxy(methyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.57 g, 3.54 mmol) in anhydrous tetrahydrofuran (15 mL) was added methylmagnesium iodide (3.54 ml, 10.62 mmol) dropwise at 0 C. The reaction mixture was stirred in the cold for 1 h, and then quenched by addition of 1 M HCl (14.17 ml, 14.17 mmol). The mixture was extracted with a mixture of ethyl acetatepetroleum ether (1:1). The organic phase was washed with brine, dried over MgSO.sub.4, filtered and evaporated to give 1.34 g of yellow oil. Yield: 86%.
Step 8: 1-((1R,5S)-5-(5-bromo-2-fluorophenyl)-3-azabicyclo[3.1.0]hexan-2-yl)ethan-1-one hydrochloride

##STR00067##

To a stirred solution of (1S,5R)-tert-butyl 4-acetyl-1-(5-bromo-2-fluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.33 g, 3.34 mmol) was added 4 M HCl in dioxane (6.68 mL, 26.7 mmol) and then the mixture was stirred at room temperature for 2 h. Thereupon, diethyl ether was added and the mixture was evaporated to dryness to give an orange oil. Yield: 1.2 g, 91%.
Step 9: (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-methyl-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione

##STR00068##

To a stirred solution of 1-((1R,5S)-5-(5-bromo-2-fluorophenyl)-3-azabicyclo[3.1.0]hexan-2-yl)ethanone hydrochloride (1.1 g, 3.29 mmol) in a mixture of ethanol (13.5 mL) and water (13.5 mL) was added potassium thiocyanate (0.351 g, 3.62 mmol) followed by addition of cc. HCl (0.135 mL, 1.644 mmol). The solution was heated at reflux for 1 h. The reaction was cooled to room temperature, and then ethanol was removed. The aqueous phase was extracted with dichloromethane, the organic phase was dried over MgSO.sub.4, filtered and evaporated. Chromatography in a mixture of dichloromethanemethanol afforded the titled compound as a beige foam. Yield: 0.9 g, 77%.
.sup.1H NMR (DMSO-d6): 11.65 (1H, s), 7.59 (1H, dd, J=6.7, 2.5 Hz), 7.55 (1H, ddd, J=8.7, 4.5, 2.6 Hz), 7.24 (1H, dd, J=10.1, 8.7 Hz), 4.05 (1H, d, J=12.0 Hz), 3.76 (1H, d, J=12.0 Hz), 2.87 (1H, dd, J=8.3, 4.3 Hz), 2.04 (3H, s), 1.64 (1H, dd, J=8.2, 5.3 Hz), 1.12 (1H, t, J=4.8 Hz).

.SUP.13.C NMR (DMSO-d6): 161.8, 160.2, 155.7, 132.9, 132.9, 132.3, 132.2, 130.2, 129.4, 129.3, 118, 117.8, 116.2, 116.2, 114.8, 51.5, 51.5, 32.2, 22.2, 20.2, 9.3.

[0162] Example 14: (5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-1-methyl-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione

##STR00069##

Compound was prepared in an analogous manner to Example 13 from 2-(3-chloro-2,6-difluorophenyl)acetonitrile. The product was isolated as a beige solid.

.SUP.1.H NMR (DMSO-d6): 11.68 (1H, s), 7.63 (1H, td, J=8.6, 5.8 Hz), 7.21 (1H, t, J=8.6 Hz), 4.01 (1H, d, J=12.2 Hz), 3.72 (1H, d, J=12.2 Hz), 2.73 (1H, dd, J=8.2, 4.4 Hz), 2.05 (3H, s), 1.65 (1H, dd, J=8.2, 5.6 Hz), 1.25 (1H, t, J=5.0 Hz).

.SUP.13.C NMR (DMSO-d6): 161.2, 161.2, 159.6, 159.6, 157.8, 157.8, 156.2, 156.1, 155.7, 130.3, 130.2, 129.9, 117.2, 117.1, 117, 115.7, 115.7, 115.6, 115.6, 115.1, 112.9, 112.9, 112.8, 112.8, 51.4, 26.4, 21.7, 20.8, 9.4.

[0163] Example 15: (R)-6-(3-bromo-2,6-difluorophenyl)-1-methyl-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

##STR00070##

Compound was prepared in an analogous manner to Example 20 from 3-bromo-2,6-difluorobenzaldehyde and isolated as a beige powder.
.sup.1H NMR (DMSO-d6): 11.73 (1H, br s), 7.72 (1H, ddd, J=8.9, 8.1, 5.8 Hz), 7.16 (1H, m), 4.44 (1H, quin, J=8.6 Hz), 4.13 (1H, dd, J=11.5, 9.2 Hz), 3.71 (1H, dd, J=11.6, 7.9 Hz), 3.23 (1H, dd, J=15.5, 9.3 Hz), 2.84 (1H, dd, J=15.4, 8.1 Hz), 1.97 (3H, s).

.SUP.13.C NMR (DMSO-d6): 160.8, 160.8, 159.2, 159.1, 157.5, 157.5, 155.9, 155.8, 155, 132.4, 132.4, 127.7, 118.8, 118.7, 118.6, 115.1, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 48.5, 35.8, 28.7, 9.3.

[0164] Example 16: (S)-6-(3-bromo-2,6-difluorophenyl)-1-methyl-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

##STR00071##

Compound was prepared in an analogous manner to Example 20 from 3-bromo-2,6-difluorobenzaldehyde using 4-((R)-hydroxy((1S,2S,4S,5R)-5-vinylquinuclidin-2-yl)methyl)quinolin-6-ol as catalyst (CAS #524-63-0) and isolated as a beige powder.
.sup.1H NMR (DMSO-d6): 11.72 (1H, br s), 7.72 (1H, ddd, J=8.9, 8.1, 5.8 Hz), 7.16 (1H, m), 4.44 (1H, t, J=8.7 Hz), 4.13 (1H, dd, J=11.5, 9.2 Hz), 3.71 (1H, dd, J=11.6, 7.9 Hz), 3.23 (1H, dd, J=15.5, 9.3 Hz), 2.84 (1H, dd, J=15.5, 8.1 Hz), 1.97 (3H, s).

.SUP.13.C NMR (DMSO-d6): 160.8, 160.8, 159.2, 159.1, 157.5, 157.5, 155.9, 155.8, 155, 132.4, 132.4, 127.7, 118.8, 118.7, 118.6, 115.1, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 48.5, 35.8, 28.7, 9.3.

[0165] Example 17: (5aS,6aR)-5a-(3-chloro-5-fluorophenyl)-1-methyl-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione

##STR00072##

Compound was prepared in an analogous manner to Example 13 from 2-(3-chloro-5-fluorophenyl)acetonitrile. The product was isolated as a beige solid.
.sup.1H NMR (DMSO-d6): 11.64 (1H, s), 7.30 (1H, dt, J=8.7, 2.1 Hz), 7.28 (1H, t, J=1.6 Hz), 7.23 (1H, dt, J=10.0, 1.8 Hz), 4.19 (1H, d, J=12.2 Hz), 3.99 (1H, d, J=12.0 Hz), 3.00 (1H, dd, J=8.3, 4.3 Hz), 2.03 (3H, s), 1.64 (1H, dd, J=8.3, 5.2 Hz), 1.14 (1H, t, J=4.8 Hz).

.SUP.13.C NMR (DMSO-d6): 163.1, 161.4, 156, 145, 144.9, 134.1, 134.1, 130.2, 123, 123, 114.5, 114.3, 114.1, 112.9, 112.8, 50.8, 36, 36, 25.2, 22.2, 9.3.

[0166] Example 18: (5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-(methyl-d.sub.3)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione

##STR00073##

Compound was prepared in an analogous manner to Example 13 from 2-(5-bromo-2-fluorophenyl)acetonitrile. The product was isolated as a beige solid.
.sup.1H NMR (DMSO-d6): 11.65 (1H, s), 7.59 (1H, dd, J=6.7, 2.6 Hz), 7.55 (1H, ddd, J=8.7, 4.5, 2.6 Hz), 7.23 (1H, dd, J=10.1, 8.7 Hz), 4.05 (1H, d, J=12.0 Hz), 3.76 (1H, d, J=12.0 Hz), 2.87 (1H, dd, J=8.2, 4.3 Hz), 1.64 (1H, dd, J=8.3, 5.4 Hz), 1.12 (1H, t, J=4.8 Hz).

.SUP.13.C NMR (DMSO-d6): 161.8, 160.2, 155.7, 132.9, 132.9, 132.3, 132.2, 130.3, 129.4, 129.3, 118, 117.8, 116.2, 116.2, 114.7, 51.5, 51.5, 32.3, 22.2, 20.2.

[0167] Example 19: (S)-6-(5-bromo-2-fluorophenyl)-1-methyl-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

##STR00074##

Compound was prepared in an analogous manner to Example 20 from 5-bromo-2-fluorobenzaldehyde using 4-((R)-hydroxy((1S,2S,4S,5R)-5-vinylquinuclidin-2-yl)methyl)quinolin-6-ol as catalyst (CAS #524-63-0) and isolated as an off-white solid.
.sup.1H NMR(DMSO-d6): 11.70 (1H, br s), 7.58 (1H, dd, J=6.7, 2.5 Hz), 7.53 (1H, ddd, J=8.7, 4.5, 2.5 Hz), 7.23 (1H, dd, J=10.3, 8.8 Hz), 4.20 (1H, quin, J=8.1 Hz), 4.11 (1H, dd, J=10.9, 8.1 Hz), 3.71 (1H, dd, J=11.3, 7.9 Hz), 3.18 (1H, dd, J=15.2, 8.1 Hz), 2.85 (1H, ddd, J=15.2, 8.3, 1.2 Hz), 1.98 (3H, s).

.SUP.13.C NMR(DMSO-d6): 160.3, 158.7, 155.1, 131.8, 131.8, 131.4, 131.4, 130.6, 130.5, 127.5, 118, 117.9, 116.5, 116.4, 115.4, 49, 40.5, 29, 9.3.

[0168] Example 20: (R)-1-methyl-6-(2,3,6-trifluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione

##STR00075##

Step 1: (E)-1,2,4-trifluoro-3-(2-nitrovinyl)benzene

##STR00076##

To a solution of methanol (90 mL) and 1.5 M sodium hydroxide (131 mL, 197 mmol) was added a solution of 2,3,6-trifluorobenzaldehyde (30 g, 187 mmol) and nitromethane (16 mL, 299 mmol) in methanol (60 mL) dropwise over 40 min at 5 C., while the internal temperature was maintained between 5 and 10 C. with external cooling. The reaction was then agitated in the cold for 30 min., and then a solution of acetic acid (16 mL, 281 mmol) was added in one portion at 0-10 C. with stirring. The resulting mixture extracted with dichloromethane (ca. 200 mL), the organic phase was washed with brine, dried (MgSO.sub.4), filtered to give 1-(3-bromo-2,6-difluorophenyl)-2-nitroethanol solution in dichloromethane. Thereupon, the above solution (ca. 270 mL) was treated with N,N-dimethylpyridin-4-amine (2.289 g, 18.74 mmol) followed by addition of acetic anhydride (21.26 ml, 225 mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was then washed with water and sodium bicarbonate solution, respectively. The organic phase was dried over MgSO.sub.4, filtered and evaporated to dryness. The crude product was crystallized from a mixture of isopropanol and water to give a light brownish solid. Yield: 38.1 g, 88%.
Step 2: diethyl (R)-2-(2-nitro-1-(2,3,6-trifluorophenyl)ethyl)malonate

##STR00077##

To a cold solution of (E)-1,2,4-trifluoro-3-(2-nitrovinyl)benzene (5 g, 24.62 mmol) and 1-(3,5-bis(trifluoromethyl)phenyl)-3-((1R,2R)-2-(dimethylamino)cyclohexyl)thiourea (CAS #620960-26-1) (0.305 g, 0.738 mmol) in dry toluene (40 ml) was added diethyl malonate (4.88 mL, 32.0 mmol) and the solution was kept for 16 h at -20 C. (in the freezer), the reaction was then warmed up to room temperature, washed with 30 mL of 1 M HCl solution, dried over MgSO.sub.4, filtered through a silica pad and evaporated to dryness to give (R)-diethyl 2-(2-nitro-1-(2,3,6-trifluorophenyl)ethyl)malonate as a yellowish oil. Yield: 10.3 g, 98%.
Step 3: ethyl (4R)-2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidine-3-carboxylate

##STR00078##

[0169] To a suspension of (R)-diethyl 2-(2-nitro-1-(2,3,6-trifluorophenyl)ethyl)malonate (10.3 g, 22.68 mmol) in methanol (115 mL) was added nickel(II) chloride hexahydrate (5.39 g, 22.68 mmol) followed by addition of sodium borohydride (6.86 g, 181 mmol) in portions with ice cooling over 30 min. The mixture was stirred for 5 h at room temperature, then quenched with 2 M HCl solution (60 mL) followed by addition of cc. ammonia (5 mL). The mixture was then diluted with dichloromethane (150 mL), acidified with 6 M HCl to pH=2, and stirred for 16 h to give a clear solution. Thereupon, the mixture was extracted with dichloromethane, the organic phase was dried over MgSO.sub.4, filtered and evaporated to dryness. Crystallization from petroleum ether gave the titled product as a light beige powder. (Yield: 6.19 g, 95%).

Step 4: (4R)-2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidine-3-carboxylic acid

##STR00079##

To a stirred solution (4R)-ethyl 2-oxo-4-(2,3,6-trifluorophenyl)pyrrolidine-3-carboxylate (6 g, 20.89 mmol) in ethanol (90 mL) was added 1 M sodium hydroxide (25.1 mL, 25.1 mmol). The resulting suspension was stirred for 2 h at room temperature, the organics were then removed under vacuum, and the residue was dissolved in water (50 mL). The product was crystallized on acidification with 6 M HCl. The resulting crystals were collected, washed with cold water and dried under vacuum at 50 C. to give the product as a beige powder. Yield: 4.75 g, 88%.
Step 5: (R)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one

##STR00080##

A solution of (4R)-2-oxo-4-(2,3,6-trifluorophenyl)pyrrolidine-3-carboxylic acid (4.64 g, 17.90 mmol) in toluene (150 mL) was stirred under reflux for 3 h, thereupon, the mixture was evaporated to 30 mL followed by addition of petroleum ether afforded the titled product as a beige powder. Yield: 3.45 g, 90%.
Step 6: tert-butyl (R)-2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidine-1-carboxylate

##STR00081##

To a stirred solution of (R)-4-(2,3,6-trifluorophenyl)pyrrolidin-2-one (3.35 g, 15.57 mmol)) in dry dichloromethane (14 mL) was added at room temperature di-tert-butyl dicarbonate (5.10 g, 23.35 mmol) followed by addition of N,N-dimethylpyridin-4-amine (1.902 g, 15.57 mmol). The mixture was then stirred at room temperature for 24 h at room temperature, and then diluted with dichloromethane to 80 mL washed with 10% citric acid (80 mL). The organic phase was dried (MgSO.sub.4), filtered through silica pad, and then the filtrate was evaporated to dryness. Crystallization from petroleum ether afforded (R)-tert-butyl 2-oxo-4-(2,3,6-trifluorophenyl)pyrrolidine-1-carboxylate as an off-white powder. Yield: 4.15 g, 85%.
Step 7: tert-butyl (4R)-2-hydroxy-4-(2,3,5-trifluorophenyl)pyrrolidine-1-carboxylate

##STR00082##

To a stirred solution of (R)-tert-butyl 2-oxo-4-(2,3,6-trifluorophenyl)pyrrolidine-1-carboxylate (4 g, 12.69 mmol) in a mixture of dry diethyl ether (39 mL) and tetrahydrofuran (13 mL) was added dropwise 65% RED-Al (bis(2-methoxyethoxy)aluminum(III) sodium hydride) (2.67 mL, 8.88 mmol) in toluene at 5-7 C. under nitrogen and the mixture was stirred for 1 h in the cold. Thereupon, the mixture was quenched with sodium bicarbonate solution (ca. 40 mL) and stirred for 30 min. The organic phase was dried over MgSO.sub.4, filtered and evaporated to dryness to give the product as a yellowish oil. (Yield: 4.55 g, 96%).
Step 8: tert-butyl (4R)-2-cyano-4-(2,3,5-trifluorophenyl)pyrrolidine-1-carboxylate

##STR00083##

To a stirred solution of (4R)-tert-butyl 2-methoxy-4-(2,3,6-trifluorophenyl)pyrrolidine-1-carboxylate (4.33 g, 11.76 mmol) in dry dichloromethane (90 mL) was added trimethylsilanecarbonitrile (3.15 mL, 23.52 mmol) followed by addition of boron trifluoride diethyl etherate (3.28 mL, 25.9 mmol) at -70 C. The mixture was stirred for 4 h in the cold, quenched with sodium bicarbonate solution, and then allowed to warm up with stirring to room temperature. The organic phase was dried over MgSO.sub.4, filtered and evaporated to dryness under vacuum to give the titled compound as a yellowish oil. (Yield: 4.41 g, 98%).
Step 9: tert-butyl (4R)-2-carbamoyl-4-(2,3,6-trifluorophenyl)pyrrolidine-1-carboxylate

##STR00084##

To a stirred solution of (4R)-tert-butyl 2-cyano-4-(2,3,6-trifluorophenyl)pyrrolidine-1-carboxylate (4.4 g, 11.46 mmol) in a mixture of acetone (54 mL) and water (18 mL) was added urea hydrogen peroxide complex (5.39 g, 57.3 mmol) followed by potassium carbonate (0.317 g, 2.292 mmol) and the reaction was stirred at room temperature for 16 h. Acetone was then partially removed under vacuum until oil separation. The mixture was diluted with water and petroleum ether, aged with stirring for 1 h at 5-7 C. (crystallization occurred). The solid was collected, washed with water, petroleum ether and dried to give (4R)-tert-butyl 2-carbamoyl-4-(2,3,6-trifluorophenyl)pyrrolidine-1-carboxylate. Yield: 3.46 g, 88%.
Step 10: (4R)-1-(tert-butoxycarbonyl)-4-(2,3,6-trifluorophenyl)pyrrolidine-2-carboxylic acid

##STR00085##

A stirred suspension of (4R)-tert-butyl 2-carbamoyl-4-(2,3,6-trifluorophenyl)pyrrolidine-1-carboxylate (3.36 g, 9.76 mmol) in 2 M HCl (73 mL, 146 mmol) was refluxed for 3 h to give a clear solution with minimum amount of dark insoluble material. After being cooled to room temperature the solid was filtered off and the filtrate was concentrated under vacuum. The residue was dissolved in water (ca. 50 mL), the pH was adjusted to 7 by addition of 1 M NaOH (19.52 mL, 19.52 mmol). The solution was then concentrated to approx. 50 mL and methanol (55 mL) was added followed by addition of di-tert-butyl dicarbonate (2.343 g, 10.73 mmol) and the mixture was stirred for 45 min. Methanol was then removed under vacuum, the residue was diluted with water (25 mL) and washed with petroleum ether. The aqueous phase was acidified to pH=1-2 by addition of 2 M HCl, and then extracted with DCM (50 m1). The organic phase was dried over MgSO.sub.4, filtered and evaporated to dryness to give (4R)-1-(tert-butoxycarbonyl)-4-(2,3,6-trifluorophenyl)pyrrolidine-2-carboxylic acid as a light beige powder. Yield: 2.8 g, 83%.
Step 11-14: (R)-1-methyl-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

##STR00086##

Compound was prepared in an analogous manner to Example 13 (Steps 6-9) from (4R)-1-(tert-butoxycarbonyl)-4-(2,3,6-trifluorophenyl)pyrrolidine-2-carboxylic acid and isolated as an off-white powder.
.sup.1H NMR (DMSO-d6): 11.72 (1H, br s), 7.47 (1H, qd, J=9.4, 5.0 Hz), 7.17 (1H, tdd, J=9.6, 9.6, 3.7, 1.9 Hz), 4.43 (1H, quin, J=8.7 Hz), 4.14 (1H, dd, J=11.3, 9.2 Hz), 3.73 (1H, dd, J=11.5, 8.1 Hz), 3.24 (1H, dd, J=15.6, 9.2 Hz), 2.86 (1H, dd, J=15.4, 8.4 Hz), 1.97 (3H, s).
.sup.13C NMR (DMSO-d6): 156.9, 156.9, 156.9, 156.9, 155.3, 155.3, 155.3, 155.3, 155, 149.1, 149, 149, 148.9, 147.5, 147.5, 147.4, 147.4, 147.3, 147.3, 145.9, 145.9, 145.8, 145.8, 127.6, 118.9, 118.8, 118.8, 118.7, 116.5, 116.4, 116.3, 116.3, 115.2, 112, 112, 111.9, 111.9, 111.8, 111.8, 111.8, 111.7, 48.4, 35.7, 28.6, 9.3.
Example 21: (R)-6-(5-bromo-2-fluorophenyl)-1-methyl-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

##STR00087##

Compound was prepared in an analogous manner to Example 20 from 5-bromo-2-fluorobenzaldehyde and isolated as an off-white solid.
.sup.1H NMR (DMSO-d6): 11.70 (1H, br s), 7.58 (1H, dd, J=6.6, 2.5 Hz), 7.53 (1H, ddd, J=8.7, 4.5, 2.5 Hz), 7.23 (1H, dd, J=10.3, 8.7 Hz), 4.20 (1H, quin, J=8.1 Hz), 4.11 (1H, dd, J=10.9, 8.2 Hz), 3.71 (1H, dd, J=11.3, 7.9 Hz), 3.18 (1H, dd, J=15.2, 8.1 Hz), 2.85 (1H, ddd, J=15.2, 8.4, 1.1 Hz), 1.98 (3H, s).

.SUP.13.C NMR (DMSO-d6): 160.3, 158.7, 155.1, 131.8, 131.8, 131.4, 131.4, 130.6, 130.5, 127.6, 118, 117.9, 116.5, 116.4, 115.4, 49, 40.5, 29, 9.3.

[0170] Example 22: (R)-6-(2,6-difluorophenyl)-1-methyl-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

##STR00088##

Compound was prepared in an analogous manner to Example 20 from 2,6-difluorobenzaldehyde and isolated as an off-white solid.
.sup.1H NMR (DMSO-d6): 11.72 (1H, br s), 7.40 (1H, tt, J=8.4, 6.6 Hz), 7.13 (2H, m), 4.41 (1H, quin, J=8.8 Hz), 4.12 (1H, m), 3.70 (1H, dd, J=11.4, 8.4 Hz), 3.21 (1H, dd, J=15.2, 9.2 Hz), 2.84 (1H, dd, J=15.4, 8.7 Hz), 1.97 (3H, s).

.SUP.13.C NMR (DMSO-d6): 161.6, 161.6, 160, 159.9, 155, 129.8, 129.7, 129.7, 127.8, 116.6, 116.5, 116.4, 115.2, 112.3, 112.2, 112.1, 112.1, 48.6, 35.4, 28.8, 9.3.

[0171] Example 23: (S)-6-(5-chloro-2-fluorophenyl)-1-methyl-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-thione

##STR00089##

Compound was prepared in an analogous manner to Example 20 from 5-chloro-2-fluorobenzaldehyde using 4-((R)-hydroxy((1S,2S,4S,5R)-5-vinylquinuclidin-2-yl)methyl)quinolin-6-ol as catalyst (CAS #524-63-0) and isolated as a beige solid.
.sup.1H NMR (DMSO-d6): 11.70 (1H, br s), 7.46 (1H, dd, J=6.5, 2.7 Hz), 7.40 (1H, ddd, J=8.8, 4.4, 2.6 Hz), 7.29 (1H, dd, J=10.1, 8.8 Hz), 4.20 (1H, quin, J=8.1 Hz), 4.11 (1H, dd, J=10.8, 8.1 Hz), 3.72 (1H, dd, J=11.3, 7.9 Hz), 3.18 (1H, dd, J=15.1, 8.1 Hz), 2.85 (1H, ddd, J=15.2, 8.3, 1.2 Hz), 1.98 (3H, s).

.SUP.13.C NMR (DMSO-d6): 159.8, 158.2, 155.1, 130.2, 130.1, 128.9, 128.8, 128.5, 128.5, 127.6, 117.6, 117.4, 115.5, 49.1, 49.1, 40.5, 29, 9.3.

G. Dopamine--Hydroxylase Inhibition Assays

[0172] The ability of a compound to inhibit DH activity may be assessed using the following cell assay. For the purposes of the present invention, a compound is considered to be a DH inhibitor if it exhibits activity in % of control of 20% at 10 m in this cell assay. Preferred compounds of the present invention (including most of the specific Examples above) exhibit activity in % of control of 50% at 1.0 m in this cell assay. More preferred compounds of the present invention exhibit activity in % of control of 20% at 1.0 m in this cell assay. Especially preferred compounds of the present invention exhibit activity in % of control of 50% at 100 nm in this assay.

[0173] SKNSH cells (ATCC HTB-11), obtained from LGC Standards (Teddington, UK) were cultured in Eagle's minimum essential medium supplemented with 25 mM Hepes, 100 U/mL penicillin G, 0.25 g/mL amphotericin B, 100 g/mL streptomycin and 10% Gibco fetal bovine serum. Cells were grown in T162 cm flasks (Corning, N.Y.) in a humidified atmosphere of 5% CO.sub.2-95% air at 37 C. Fetal bovine serum was removed from cells for 4 h prior to collection.

[0174] For the preparation of cellular homogenates, media was removed and cell monolayers were washed with 50 mM Tris-HCl pH 7.4. Cells were subsequently scrapped off the flasks and were resuspended in 50 mM Tris pH 7.4. Cell suspensions were homogenized with SilentCrusher M (Heidolph) for a short stroke and resultant homogenates were aliquoted and stored frozen at 80 C.

[0175] Total protein was quantified in cellular homogenates with BioRad Protein Assay (BioRad) using a standard curve of BSA (50-250 g/mL).

[0176] DH activity was measured by a modification of the method of Nagatsu and Udenfriend (Nagatsu, T. and S. Udenfriend: Photometric assay of dopamine-hydroxylase activity in human blood. Clin. Chem. 18(9): 980-3, 1972) which is based on the enzymatic hydroxylation of tyramine into octopamine. The octopamine formed is subsequently oxidized to p-hydroxybenzaldehyde and measured by spectrophotometry. In brief, reaction mixture (total volume 500 l) contained: cellular homogenate (75 g total protein) sodium acetate pH 5.0 (200 mM), NEM (30 mM), CuSO.sub.4 (5 M), catalase aqueous solution (0.5 mg/mL), pargyline-HCl (1 mM), sodium fumarate (10 mM), ascorbic acid (10 mM), inhibitor or vehicle and tyramine (25 mM). After a 10 min pre-incubation period at 37 C., the reaction was initiated by the addition of tyramine. Reaction was carried out for 45 min at 37 C. before termination with 50 l PCA (2 M). Samples were centrifuged for 3 min at 16100 g and supernatants were subjected to solid phase extraction. Solid phase extraction was performed using either SPE cartridges ISOLUTE SCX-3 (100 mg, 1 mL) or SPE 2 mL fixed 96 well plates ISOLUTE SCX-3 (100 mg) previously equilibrated with MilliQ water. Columns/plates were centrifuged at 150 g for 2 min. Eluate was discarded and matrix was washed with 1 mL of MilliQ water after which octopamine was eluted with 20.25 mL ammonium hydroxide (4 M). The oxidation of octopamine to p-hydroxybenzaldehyde was carried out for 6 min with 100 l sodium periodate (2%) and was stopped with 100 l sodium metabisulfite (10%). Absorbance was measured at 330 nm on a

[0177] Spectramax microplate reader (Molecular Devices, Sunnyvale, Calif.). All enzymatic reactions were performed in duplicate. Results are reported in the table below as activity in % of control at the inhibitor concentration tested.

[0178] Furthermore, the ability of a compound to inhibit DH activity may be assessed in human plasma using the following assay. For the purposes of the present invention, a compound is considered to be a DH inhibitor if it exhibits activity in % of control of 20% at 10 m in this assay. Preferred compounds of the present invention (including most of the specific Examples above) exhibit activity in % of control of 50% at 1.0 m in this cell assay. More preferred compounds of the present invention exhibit activity in % of control of 20% at 1.0 m in this cell assay. Especially preferred compounds of the present invention exhibit activity in % of control of 50% at 100 nm in this assay.

[0179] Dopamine beta hydroxylase activity in human plasma was measured by the method previously developed (Nagatsu, T. and Udenfriend, S. Photometric assay of dopamine--hydroxylase activity in human blood. Clin. Chem. 18(9) 980-983, 1972) with minor modifications. Catalase, N-ethylmaleimide, tyramine, disodium fumarate, pargyline, sodium acetate, ascorbic acid, copper sulfate and octopamine were obtained from Sigma Chemical Co., St. Louis, Mo. 63178. Human plasma samples were obtained from healthy donors (Instituto Portugus do Sangue Transplantao, Centro Sangue Transplantao, Porto, Portugal). From date of collection, plasma was stored at 80 C. until use. Test compounds were initially prepared in dimethyl sulfoxide at a concentration of 10 mM and diluted in dimethyl sulfoxide to the required concentrations. Test compounds were further diluted in ultrapure water to a concentration 20-fold to that of the final concentration to be tested. Final concentrations of test compounds were 10, 100 and 1000 nM. The various reagents used to make up the incubation buffer were premixed and consisted of the following components: sodium acetate buffer (1 M, pH 5.0, 18 ml), sodium fumarate (0.2 M, 4.5 ml), ascorbic acid (0.2 M, 4.5 ml, freshly prepared), pargyline (20 mM, freshly prepared, 4.5 ml), N-ethylmaleimide (0.2 M, 4.5 ml), catalase (10 000 U/ml, 9 ml), copper sulfate (20 M, 4.5 ml) and 4.5 ultrapure water. The standard incubation mixture (total volume, 950 l) contained: 50 L of compound or vehicle (dimethyl sulfoxide 2%); 700 L of incubation buffer; 125 l of plasma (or saline for blank reaction or standard curve); 75 l of saline. The reaction mixture was placed in water bath, shaking at 37 C. and pre-incubated for 10 minutes. Tyramine (0.5 M) was added and incubation proceeded for 45 minutes. The reaction contents were exposed to air. A sample of enzyme preparation (with 125 l of plasma) that had been added perchloric acid 2 M at the end of the pre-incubation period was used as blank. A blank for each of the tested compounds was used. For octopamine standard curve, perchloric acid 2 M was replaced by increasing concentrations of octopamine prepared in perchloric acid 2 M (0.5, 1, 2.5, 5, 7.5, 10, 15, 20 g/ml, final concentration). The incubation was stopped by adding 200 l of 2 M molar perchloric acid, and the mixture was centrifuged at 9000 g for 5 min. The supernatant fluid (800 L) was transferred to a column (SPE cartridge ISOLUTE SCX-3, 100 mg) and centrifuged at 150 g for 2 min. The column was washed two more times with 0.5 ml of ultrapure water by centrifuging at 150 g for 2 min. The adsorbed octopamine was eluted twice with 0.3 ml of 4 M ammonium hydroxide by centrifuging at 150 g for 2 min. Octopamine in the eluate was then converted to p-hydroxybenzaldehyde by adding 200 l of sodium periodate (2%) and incubating for 6 min. Excess periodate was than reduced by adding 200 l of sodium metabisulfite (10%). Absorbance was measured at 330 mm in a 96-well plate by use of a SpectraMAX plus 384 (Molecular Devices) with software SOFTmax PRO Software 5.3 spectrophotometer. Absorbance was linear with octopamine concentration from 0.5 to 20 g/ml. Dopamine beta hydroxylase activity is determined as nmol of octopamine formed/ml of plasma/hour and effect of compounds is presented as % control.

[0180] Results are reported in the table below (inside brackets) as activity in % of control at the inhibitor concentration tested.

H. Biological Data

[0181] In Vitro Experiments:

TABLE-US-00001 DH activity in DH activity in % of Ctrl % of Ctrl Example (0.1 M) (1 M) 1 10.9 2 13.0 3 56.7 4 28.9 5 32.0 (57.3)* 15.0 6 41.9 (74.1)* 7.9 7 39.9 8 31.6 (38.3)* 1 9 0 0 10 47.5 6.0 11 17.4 0 12 5.2 0 13 (9.8)* 14 (4.7)* 15 (23.8)* 16 (12.1)* 17 (49.9)* 18 (10.0)* 19 (39.1)* 20 (27.7)* 21 (88.8)* 22 (0.5)* 23 (67.0)* *numbers in brackets represent activity in % of control in human plasma assay