LV13469B

LV13469B - Treatment of latent tuberculosis

Info

Publication number: LV13469B
Application number: LVP-05-161A
Authority: LV
Inventors: Koenraad Jozef Lodewij Andries; Anil Koul
Original assignee: Janssen Pharmaceutica Nv
Priority date: 2004-12-24
Filing date: 2005-12-09
Publication date: 2007-01-20
Also published as: NO340376B1; HRP20110392T1; BRPI0506400A; MY145845A; EE200500033A; IL184123A0; TW200637551A; EE05394B1; BRPI0506400B8; EP1830850B1; PT1830850E; TR200504892A1; AR051790A1; CA2529265C; BRPI0506400A8; CN103142595A; BRPI0506400B1; NZ555460A; AU2005242138B2; NO20073823L

Description

IZGUDROJUMA FORMULA

Savienojuma ar formulu (la) vai (Ib) izmantošana medikamenta ražošanai latentās tuberkulozes ārstēšanai, pie kam savienojums ar formulu (la) vai (Ib) ir

tā farmaceitiski pieņemams pievienotas skābes vai bāzes sāls, tā ceturtējais amīns, tā /V-oksīds, tā tautomēra vai stereoķīmiski izomēra forma, kur R¹ ir ūdeņraža atoms, halogēna atoms, halogēnalkilgrupa, ciāngrupa, hidroksilgrupa, Ar, Het, alkilgrupa, alkiloksigrupa, alkiltiogrupa, alkiloksialkilgrupa, alkiltioalkilgrupa, Ar-alkilgrupa vai di(Ar)a!kilgrupa;

p ir vesels skaitlis, kas vienāds ar 1, 2, 3 vai 4;

R² ir ūdeņraža atoms, hidroksilgrupa, merkaptogrupa, alkiloksigrupa, alkiloksialkiloksigrupa, alkiltiogrupa, mono- vai di(alkil)aminogrupa vai grupa ar formulu kur Y ir CH₂, O, S, NH vai ΛΑ-alkilgrupa;

R³ ir alkilgrupa, Ar, Ar-alkilgrupa, Het vai Het-alkilgrupa;

q ir vesels skaitlis, kas vienāds ar nulli, 1, 2, 3 vai 4;

R⁴ un R⁵ katrs neatkarīgi ir ūdeņraža atoms, alkilgrupa vai benzilgrupa; vai R⁴ un R⁵ kopā un iekļaujot N atomu, pie kā tie saistīti, var veidot grupu, kas izvēlēta no pirolidinilgrupas, 2-pirolinilgrupas, 3-pirolinilgrupas, pirolilgrupas, imidazolidinilgrupas, pirazolidinilgrupas, 2imidazolinilgrupas, 2-pirazolinilgrupas, imidazolilgrupas, pirazolilgrupas, triazolilgrupas, piperidinilgrupas, piridinilgrupas, piperazinilgrupas, piridazinilgrupas, pirimidinilgrupas, pirazinilgrupas, triazinilgrupas, morfolinilgrupas un tiomorfolinilgrupas, pie kam katra no minētajām cikliskajām sistēmām ir neobligāti aizvietota ar alkilgrupu, halogēna atomu, halogēnalkilgrupu, hidroksilgrupu, alkiloksigrupu, aminogrupu, mono- vai diaikilaminogrupu, aikiltiogrupu, alkiloksialkilgrupu, alkiltioalkilgrupu un pirimidinilgrupu;

R⁶ ir ūdeņraža atoms, halogēna atoms, halogēnalkilgrupa, hidroksilgrupa, Ar, alkilgrupa, alkiloksigrupa, alkiltiogrupa, alkiloksialkilgrupa, alkiltioalki Ig rupa, Ar-alkilgrupa vai di(Ar)alkilgrupa; vai divas blakus esošas R⁶ grupas var tikt ņemtas kopā, lai veidotu divvērtīgu grupu ar formulu -CH=CH-CH=CH-; r ir vesels skaitlis, kas vienāds ar 1, 2, 3, 4 vai 5;

R⁷ ir ūdeņraža atoms, alkilgrupa, Ar vai Het;

R⁸ ir ūdeņraža atoms vai alkilgrupa,

R⁹ ir oksogrupa; vai

R⁸un R⁹ kopā veido =N-CH=CH- grupu;

alkilgrupa ir lineāras vai sazarotas virknes piesātināta ogļūdeņražgrupa ar 1 līdz 6 oglekļa atomiem; vai ir cikliska piesātināta ogļūdeņražgrupa ar 3 līdz 6 oglekļa atomiem; vai ir cikliska piesātināta ogļūdeņražgrupa ar 3 līdz 6 oglekļa atomiem, kas pievienota lineāras vai sazarotas virknes piesātinātai ogļūdeņražgrupai ar 1 līdz 6 oglekļa atomiem; pie kam katrs oglekļa atoms neobligāti var būt aizvietots ar halogēna atomu, hidroksilgrupu, alkiloksigrupu vai oksogrupu;

Ar ir homocikls, kas izvēlēts no fenilgrupas, naftilgrupas, acenaftilgrupas, tetrahidronaftilgrupas, pie kam katrs homocikls neobligāti ir aizvietots ar 1, 2 vai 3 aizvietotājiem, kur katrs aizvietotājs neatkarīgi ir izvēlēts no hidroksilgrupas, halogēna atoma, ciāngrupas, nitrogrupas, aminogrupas, mono- vai dialkilaminogrupas, alkilgrupas, haiogēnalkilgrupas, alkiloksigrupas, halogēnalkiloksigrupas, karboksilgrupas, alkiloksikarbonilgrupas, aminokarbonilgrupas, morfolinilgrupas un mono- vai dialkilaminokarbonilgrupas;

Het ir monociklisks heterocikls, kas izvēlēts no ΛΑ fenoksipiperidinilgrupas, piperidinilgrupas, pirolilgrupas, pirazolilgrupas, imidazolilgrupas, furanilgrupas, tienilgrupas, oksazolilgrupas, izoskazolilgrupas, tiazolilgrupas, izotiazolilg rupas, piridinilgrupas, pirimidinilgrupas, pirazinilgrupas un piridazinilgrupas; vai biciklisks heterocikls, kas izvēlēts no hinolinilgrupas, hinoksalinilgrupas, indolilgrupas, benzimidazolilgrupas, benzoksazolilgrupas, benzizoksazolilgrupas, benztiazolilgrupas, benzizotiazolilgrupas, benzfuranilgrupas, benztienilgrupas, 2,3-dihidrobenzo[1,4]dioksinilgrupas; vai benzo[1,3]dioksolilgrupas, pie kam katrs monocikliskais un bicikliskais heterocikls var būt neobligāti aizvietots ar 1, 2 vai 3 aizvietotājiem, kas izvēlēti no halogēna atoma, hidroksilgrupas, alkilgrupas, alkiloksigrupas vai Ar15 karbonilgrupas;

halogēna atoms ir aizvietotājs, kas izvēlēts no fluora atoma, hlora atoma, broma atoma un joda atoma; un halogēnalkilgrupa ir lineāras vai sazarotas virknes piesātināta ogļūdeņražgrupa ar 1 līdz 6 oglekļa atomiem vai ir cikliska piesātināta ogļūdeņražgrupa ar 3 līdz 6 oglekļa atomiem;

pie kam viens vai vairāki oglekļa atomi ir aizvietoti ar vienu vai vairākiem halogēna atomiem.

2,

Izmantošana saskaņā ar 1. punktu, kur

R¹ ir ūdeņraža atoms, halogēna atoms, ciāngrupa, Ar, Het, alkilgrupa un alkiloksigrupa;

p ir vesels skaitlis, kas vienāds ar 1 vai 2;

R² ir ūdeņraža atoms, hidroksilgrupa, alkiloksigrupa, alkiloksialkiloksigrupa, alkiltiogrupa vai grupa ar formulu

kur Y ir O;

R³ ir alkilgrupa, Ar, Ar-alkilgrupa vai Het;

q ir vesels skaitlis, kas vienāds ar nulli, 1, 2 vai 3;

R⁴ un R⁵ katrs neatkarīgi ir ūdeņraža atoms, alkilgrupa vai benzilgrupa; vai R⁴ un R⁵ kopā un iekļaujot N atomu, pie kā tie saistīti, var veidot grupu, kas izvēlēta no pirolidinilgrupas, imidazolilgrupas, triazolilgrupas, piperidinilgrupas, piperazinilgrupas, pirazinilgrupas, morfolinilgrupas un tiomorfolinilgrupas, pie kam katra no cikla sistēmām ir neobligāti aizvietota ar alkilgrupu vai pirimidinilgrupu;

R⁶ ir ūdeņraža atoms, halogēna atoms vai alkilgrupa vai divas blakus esošas R⁶ grupas var tikt ņemtas kopā, lai veidotu divvērtīgu grupu ar formulu -CH=CH-CH=CH-;

r ir vesels skaitlis, kas vienāds ar 1;

R⁷ ir ūdeņraža atoms;

R⁸ ir ūdeņraža atoms vai alkilgrupa,

R⁹ ir oksogrupa; vai

R⁸un R⁹ kopā veido =N-CH=CH- grupu;

alkilgrupa ir lineāras vai sazarotas virknes piesātināta ogļūdeņražgrupa ar 1 līdz 6 oglekļa atomiem; vai ir cikliska piesātināta ogļūdeņražgrupa ar 3 līdz 6 oglekļa atomiem; vai ir cikliska piesātināta ogļūdeņražgrupa ar 3 līdz 6 oglekļa atomiem, kas pievienota lineāras vai sazarotas virknes piesātinātai ogļūdeņražgrupai ar 1 līdz 6 oglekļa atomiem; pie kam katrs oglekļa atoms neobligāti var būt aizvietots ar halogēna atomu vai hidroksilgrupu;

Ar ir homocikls, kas izvēlēts no fenilgrupas, naftilgrupas, acenaftilgrupas, tetrahidronaftilgrupas, pie kam katrs homocikls neobligāti ir aizvietots ar 1, 2 vai 3 aizvietotājiem, kur katrs aizvietotājs neatkarīgi ir izvēlēts no halogēna atoma, halogēnalkilgrupas, ciāngrupas, alkiloksigrupas un morfolinilgrupas;

Het ir monociklisks heterocikls, kas izvēlēts no Nfenoksipiperidinilgrupas, piperidinilgrupas, furanilgrupas, tienilgrupas, piridinilgrupas, pirimidinilgrupas, vai biciklisks heterocikls, kas izvēlēts no benztienilgrupas, 2,3dihidrobenzoļl ,4]dioksinilgrupas vai benzo[1,3]dioksolilgrupas; pie kam katrs monocikliskais un bicikliskais heterocikls var būt neobligāti aizvietots ar 1, 2 vai 3 alkilgrupām vai Arkarbonilgrupām; un halogēna atoms ir aizvietotājs, kas izvēlēts no fluora atoma, hlora atoma un broma atoma.

Izmantošana saskaņā ar 1. vai 2. punktu, kur formulā (la) vai (Ib) R¹ ir ūdeņraža atoms, halogēna atoms, Ar, alkilgrupa vai alkiloksigrupa.

Izmantošana saskaņā ar 3. punktu, kur R¹ ir halogēna atoms.

5. Izmantošana saskaņā ar jebkuru no iepriekšējiem punktiem, kur formulā (la) vai (Ib) p ir vienāds ar 1.

6. Izmantošana saskaņā ar jebkuru no iepriekšējiem punktiem, kur formulā (la) vai (Ib) R² ir ūdeņraža atoms, alkiloksigrupa vai alkiltiogrupa.

7. Izmantošana saskaņā ar 6. punktu, kur R² ir alkiloksigrupa.

8. Izmantošana saskaņā ar jebkuru no iepriekšējiem punktiem, kur formulā (la) vai (Ib) R³ ir naftilgrupa, fenilgrupa vai tieniigrupa, pie kam katra neobligāti aizvietota ar 1 vai 2 aizvietotājiem, kas izvēlēti no halogēna atoma un halogēnalkilgrupas.

9. Izmantošana saskaņā ar 8. punktu, kur R³ ir naftilgrupa.

10. Izmantošana saskaņā ar jebkuru no iepriekšējiem punktiem, kur formulā (la) vai (Ib) q ir vienāds ar 1.

11. Izmantošana saskaņā ar jebkuru no iepriekšējiem punktiem, kur formulā (la) vai (Ib) R⁴ un R⁵ katrs neatkarīgi ir ūdeņraža atoms vai alkilgrupa vai R⁴ un R⁵ kopā un iekļaujot N atomu, pie kā tie saistīti, var veidot grupu, kas izvēlēta no imidazolilgrupas, triazolilgrupas, piperidinilgrupas, piperazinilgrupas un tiomorfolinilgrupas.

12. Izmantošana saskaņā ar 11. punktu, kur formulā (la) vai (Ib) R⁴ un R⁵ katrs neatkarīgi ir ūdeņraža atoms vai alkilgrupa.

13. Izmantošana saskaņā ar 12. punktu, kur R⁴ un R⁵ ir C₁₄alkilgrupa.

14. Izmantošana saskaņā ar jebkuru no iepriekšējiem punktiem, kur formulā (la) vai (Ib) R⁶ ir ūdeņraža atoms, alkilgrupa vai halogēna atoms.

15. Izmantošana saskaņā ar 14. punktu, kur R⁶ ir ūdeņraža atoms.

16. Izmantošana saskaņā ar jebkuru no iepriekšējiem punktiem, kur formulā (la) vai (Ib) r ir vienāds ar 1.

17. Izmantošana saskaņā ar jebkuru no iepriekšējiem punktiem, kur formulā (la) vai (Ib) R⁷ ir ūdeņraža atoms.

18. Izmantošana saskaņā ar 1. punktu, kur formulā (la) vai (lb) R¹ ir ūdeņraža atoms, halogēna atoms, Ar, alkilgrupa vai alkiloksigrupa; p=1; R² ir ūdeņraža atoms, alkiloksigrupa vai alkiltiogrupa; R³ ir naftilgrupa, fenilgrupa vai tienilgrupa, pie kam katra neobligāti aizvietota ar 1 vai 2 aizvietotājiem, kas izvēlēti no halogēna atoma un halogēnalkilgrupas; q=0, 1, 2 vai 3; R⁴ un R⁵katrs neatkarīgi ir ūdeņraža atoms vai alkilgrupa vai R⁴ un R⁵ kopā un iekļaujot N atomu, pie kā tie saistīti, var veidot grupu, kas izvēlēta no imidazolilgrupas, triazolilgrupas, piperidinilgrupas, piperazinilgrupas un tiomorfolinilgrupas; R⁶ ir ūdeņraža atoms, alkilgrupa vai halogēna atoms; r ir vienāds ar 1 un R⁷ ir ūdeņraža atoms.

19. Izmantošana saskaņā ar jebkuru no iepriekšējiem punktiem, kur alkilgrupa apzīmē Cļ^alkilgrupu.

20. Izmantošana saskaņā ar jebkuru no iepriekšējiem punktiem, kur alkilgrupa apzīmē polihalogēnC.,_₆alkilgrupu.

21. Izmantošana saskaņā ar 1. punktu, kas raksturīga ar to, ka savienojums ir izvēlēts no grupas, kas sastāv no:

- 1 -(6-brom-2-metoksihinolin-3-il)-2-(3,5-difluorfenil)-4-dimetilamino-1 fenilbutan-2-ola;

- 1-(6-brom-2-metoksihinolin-3-il)-4-dimetilamino-2-naftalen-1-il-1fenilbutan-2-ola;

- 1 -(6-brom-2-metoksihinolin-3-il)-2-(2,5-difluorfenil)-4-dimetilamino-1 fenilbutan-2-ola;

- 1 -(6-brom-2-metoksihinolin-3-il)-2-(2,3-difluorfenil)-4-dimetilamino-1 fenilbutan-2-ola;

- 1 -(6-brom-2-metoksihinolin-3-il)-4-dimetilamino-2-(2-fluorfenil)-1 fenilbutan-2-ola;

- 1 -(6-brom-2-metoksihinolin-3-il)-4-dimetilamino-2-naftalen-1 -il-1 -ptolilbutan-2-ola;

- 1 -(6-brom-2-metoksihinolin-3-il)-4-metilamino-2-nafatlenil-1 -il-1 fenilbutan-2-ola;

-1 -(6-brom-2-metoksihinoiin-3-il)-4-dimetilamino-2-(3-fluorfeni!)-1 fenilbutan-2-ola un

- 1 -(6-brom-2-metoksihinolin-3-il)-4-dimetilamino-2-fenil-1 -fenilbutan2-ola, to farmaceitiski pieņemamiem pievienotas skābes vai bāzes sāļiem, to Noksīdiem, tā tautomērām vai stereoķīmiski izomērām formām.

22. Izmantošana saskaņā ar 1. punktu, kur savienojums ir izvēlēts no grupas, kas sastāv no

- 1 -(6-brom-2-metoksihinolin-3-il)-4-dimetilamino-2-naftalen-1 -il-1 -fenilbutan2-ola, to farmaceitiski pieņemamiem pievienotas skābes vai bāzes saliem, to Noksīdiem, tā tautomērām vai stereokīmiski izomērām formām.

23. Izmantošana sakaņā ar 1. punktu, kur savienojums ir

vai tā farmaceitiski pieņemams pievienotas skābes vai bāzes sāls, ta Noksīds vai stereoķīmiski izomēra forma.

24. Izmantošana sakaņā ar 23. punktu, kur savienojums ir

vai tā farmaceitiski pieņemams pievienotas skābes sāls.

25. Izmantošana sakaņā ar 23. punktu, kur savienojums ir

vai tā stereoķīmiski izomēra forma.

26. Izmantošana sakaņā ar 23. punktu, kur savienojums ir

vai ta /V-oksīda forma.

27. Izmantošana sakaņā ar 23. punktu, kur savienojums ir

vai ta farmaceitiski pieņemams pievienotas skābes sals.

28. Izmantošana sakaņā ar 27. punktu, kur savienojums ir

-1TREATMENT OF LATENT TUBERCULOSIS

The present invention relates to the use of a compound of formula (la) or (Ib) for 5 treating latent tuberculosis.

BACKGROUND OF THE INVENTION

Mycobacterium tuberculosis results in more than 2 million deaths per year and is the 10 leading cause of mortality in people infected with HIV¹. In spite of decades of tuberculosis (TB) control programs, about 2 billion people are infected by M. tuberculosis, though asymptomatically. About 10% of these individuāls are at risk of developing active TB during their lifespan ². The global epidemic cf TB is fcelled by infection of HIV patients with TB and rise of multi-drug resistant TB strains (MDR-TB). The reactivation of latent TB is a high risk factor for disease development and accounts for 32% deaths in HIV infected individuāls¹. To control TB epidemic, the need is to discover new drugs that can kill dormant or latent TB bacilli. The dormant TB can get reactivated to cause disease by several factors like suppression of host immunity by use of immunosuppressive aģents like antibodies against tumor necrosis factor α or interferon-γ. In case of HTV positive patients the only prophylactic treatment available for latent TB is tvvo- three months regimens of rifampicin, pyrazinamide ³’⁴. The efficacy of the treatment regime is stili not clear and furthermore the length of the treatments is an important constrain in resource-limited environments. Hence there is a drastic need to identify new drugs, vvhich can act as chemoprophylatic aģents for individuāls harboring latent TB bacilli.

The tubercle bacilli enter healthy individuāls by inhalation; they are phagocytosed by the alveolar macrophages of the lungs. This leads to potent immune response and formation of granulomas, vvhich consist of macrophages infected vvith M. tuberculosis surrounded by T celis. After a period of 6-8 vveeks the host immune response cause death of infected celis by necrosis and accumulation of caseous material vvith certain extracellular bacilli, surrounded by macrophages, epitheloid celis and layers of lymphoid tissue at the periphery⁵. In case of healthy individuāls, most of the mycobacteria are killed in these environments but a small proportion of bacilli stili survive and are thought to exist in a non-replicating, hypometabolic state and are tolerant to killing by anti-TB drugs like isoniazid⁶. These bacilli can remain in the altered physiological environments even for individual’s lifetime vvithout shovving any clinical symptoms of disease. Hovvever, in 10% of the cases these latent bacilli may

-2reactivate to cause disease. One of the hypothesis about development of these persistent bacteria is patho-physiological environment in human lesions namely, reduced oxygen tension, nutrient limitation, and acidic pH⁷. These factors have been postulated to render these bacteria phenotypically tolerant to major anti-mycobacterial drugs⁷.

WO 2004/011436 describes substituted quinoline derivatives useful for the treatment of mycobacterial diseases. Said document discloses the antimycobacterial property of the substituted quinoline derivatives against sensitive, susceptible Mycobacterium strains but is silent on their activity against latent, dormant, persistent mycobacteria.

We have now found that the compounds of WO 2004/011436, in particular the compounds of formula (la) and (Ib) as defined hereinbelov/, have sterilizing properties; are effective in killing dormant, latent, persistent mycobacteria, in particular

Mycobacterium tuberculosīs, and can consequently be used to treat latent TB. They vvill therefore greatly enhance the arsenal to fight TB.

DESCRIPTION OF THE FIGURĒS

Figurē 1 : The effect of various drugs on dormant M. bovis assayed by Luciferase 20 counts (RLU : relative luminescence units) (the bacteria vvere suspended in drug free medium for 5 days after 7 days of anaerobiosis).

Figurē 2A) : The effect of various drugs on dormant M. bovis (CFU : colony forming units) (CFU determined 2 days after anaerobiosis, are reported).

Figurē 2B) : The effect of various drugs on dormant M. bovis (CFU : colony forming units) (CFU determined 5 days after anaerobiosis, are reported).

Figurē 3 : The effect of various drugs on dormant Ai tuberculosīs modei)

INVENTION

Thus, the present invention relates to the use of a compound of formula (la) or (Ib) for 30 the manufacture of a medicament for the treatment of latent tuberculosīs, vvherein the compound of formula (la) or (Ib) is

(Ia) (Ib) a pharmaceutically acceptable acid or base addition salt thereof, a quatemary amine thereof, a V-oxide thereof, a tautomeric form thereof or a stereochemically isomeric form thereof wherein

R¹ is hydrogen, halo, haloalkyl, cyano, hydroxy, Ar, Het, alkyl, alkyloxy, alkylthio, alkyloxyalkyl, alkylthioaJkyl, Ar-alkyl or di(Ar)alkyl;

p is an integer equal to 1, 2, 3 or 4 ;

R² is hydrogen, hydroxy, mercapto, alkyloxy, alkyloxyalkyloxy, alkylthio, '_XY mono or di(alkyl)amino or a radical of formula vvherein Y is

CH₂, 0, S, NH or A-alkyl;

R³ is alkyl, Ar, Ar-alkyl, Het or Het-alkyl;

q is an integer equal to zero, 1, 2, 3 or 4 ;

R⁴ and R⁵ each independently are hydrogen, alkyl or benzyl; or

R⁴ and R⁵ together and including the N to vvhich they are attached may form a radical selected from the group of pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, 2-imidazolinyl, 2-pyrazolinyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, piperazinyl,

-4pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, morpholinyl and thiomorpholinyl, each of said ring systems optionally substituted with alkyl, halo, haloalkyl, hydroxy, alkyloxy, amino, mono- or dialkylamino, alkyltbio, alkyloxyalkyl, alkyltbioalkyl and pyrimidinyl;

R⁶ is bydrogen, balo, haloalkyl, hydroxy, Ar, alkyl, alkyloxy, aikyithio, alkyloxyalkyl, alkylthioalkyl,Ar-alkyl or di(Ar)alkyl; or two viciņai R⁶ radicals may be taken together to form a bivalent radical of formula -CH=CH-CH=CH-;

r is an integer equal to 1, 2, 3, 4 or 5 ;

R⁷ is hydrogen, alkyl, Ar or Het;

o

R is hydrogen or alkyl;

R⁹ is oxo ; or

R⁸ and R⁹ together form the radical =N-CH=CH-;

alkyl is a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms ; or is a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms ; or is a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms attached to a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms ; wherein each carbon atom can be optionally substituted vvith halo, hydroxy, alkyloxy or oxo ;

Ar is a homocycle selected from the group of phenyl, naphthyl, acenaphthyl, tetrahydronaphthyl, each homocycle optionally substituted vvith 1, 2 or 3 substituents, each substituent independently selected from the group of hydroxy, halo, cyano, nitro, amino, mono- or dialkylamino, alkyl, haloalkyl, alkyloxy, haloalkyloxy, carboxyl, alkyloxycarbonyl, aminocarbonyl, morpholinyl and mono- or dialkylaminocarbonyl;

Het is a monocyclic heterocycle selected from the group of A-phenoxypiperidinyl, piperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; or a bicyclic heterocycle selected from the group of quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2,3dihydrobenzo[l,4]dioxinyl or benzo[l,3]dioxolyl; each monocyclic and bicyclic heterocycle may optionally be substituted vvith 1, 2 or 3 substituents selected from the group of halo, hydroxy, alkyl, alkyloxy, or Ar-carbonyl;

halo is a substituent selected from the group of fluoro, chloro, bromo and iodo; and haloalkyl is a straight or branched saturated hydrocarbon radical having from 1 to carbon atoms or a cyclic saturated hydrocarbon radical having from 3

-5to 6 carbon atoms, vvherein one or more carbon atoms are substituted vvith one or more halo-atoms.

The present invention also relates to a method of treating a patient, including a human, 5 with latent TB, vvhich comprises administering to the patient a therapeuticaiiy effective amount of a compound according to the invention.

The compounds according to formula (la) and (Ib) are interrelated in that e.g. a compound according to formula (Ib), with R⁹ equal to oxo is the tautomeric equivalent of a compound according to formula (la) vvith R² equal to hydroxy (keto-enol tautomerism).

In the framevvork of this application, alkyl is a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms ; or is a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms ; or is a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms attached to a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms ; vvherein each carbon atom can be optionally substituted vvith halo, hydroxy, alkyloxy or oxo.

Preferably, alkyl is methyl, ethyl or cyclohexylmethyl.

In the framevvork of this application, Ar is a homocycle selected from the group of phenyl, naphthyl, acenaphthyl, tetrahydronaphthyl, each optionally substituted vvith 1, 2 or 3 substituents, each substituent independently selected from the group of hydroxy, halo, cyano, nitro, amino, mono- or dialkylamino, alkyl, haloalkyl, alkyloxy, haloalkyloxy, carboxyl, alkyloxycarbonyl, aminocarbonyl, morpholinyl and mono- or dialkylaminocarbonyl. Preferably, Ar is naphthyl or phenyl, each optionally substituted vvith 1 or 2 halo substituents.

In the framevvork of this application, Het is a monocyclic heterocycle selected from the group of /V-phenoxypiperidinyl, piperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyTazinyl and pyridazinyl; or a bicyclic heterocycle selected from the group of quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2,3-dihydrobenzo[l,4]dioxinyl or benzo[l,3]dioxolyl; each monocyclic and bicyclic heterocycle may optionally be substituted vvith 1, 2 or 3 substituents selected from the group of halo, hydroxy, alkyl, alkyloxy or Ar-carbonyl. Preferably, Het is thienyl.

-6In the framevvork of this application, halo is a substituent selected from the group of fluoro, chloro, bromo and iodo and haloalkyl is a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms or a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms, vvherein one or more carbon atoms are substituted vvith one or more halo-atoms. Preferably, halo is bromo, fluoro or chloro and preferably, haloalkyl is polyhaloCi_6alkyl vvhich is defined as mono- or polyhalosubstituted Ci_6alkyl, for example, methyl vvith one or more fluoro atoms, for example, difluoromethyl or trifluoromethyl, l,l-difluoro-ethyl and the like. In case more than one halogen atoms are attached to an alkyl group vvithin the definition of polyhaloCi_6alkyl, they may be the same or different. Ci^alkyl is a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms such as for example methyl, ethyl, propyl, 2-methyl-ethyl, pentyl, hexyl and the like.

In the definition of Het, or vvhen R⁴ and R⁵ are taken together, it is meant to include ali the possible isomeric forms of the heterocycles, for instance, pyrrolyl comprises l//-pyrrolyl and 2//-pyrrolyl.

The Ar or Het listed in the defmitions of the substituents of the compounds of formula (la) or (Ib) (see for instance R³) as mentioned hereinbefore or hereinafter may be attached to the remainder of the molecule of formula (la) or (Ib) through any ring carbon or heteroatom as appropriate, if not othervvise specified. Thus, for example, vvhen Het is imidazolyl, it may be l-imidazolyl, 2-imidazolyl, 4-imidazolyl and the like.

Lines dravvn from substituents into ring systems indicate that the bond may be attached to any of the suitable ring atoms.

When tvvo viciņai R⁶ radicals are taken together to form a bivalent radical of formula -CH=CH-CH=CH-, this means that the tvvo viciņai R⁶ radicals form together vvith the phenyl ring to vvhich they are attached a naphthyl.

For therapeutic use, salts of the compounds of formula (la) or (Ib) are those vvherein the counterion is pharmaceutically acceptable. Hovvever, salts of acids and bases vvhich are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. Ali salts, vvhether

-7pharmaceutically acceptable or not, are included within the ambit of the present invention.

The pharmaceutically acceptable addition salts as mentioned hereinabove or hereinafter 5 are meant to comprise the therapeuticaiiy active non-toxic acid addition salt forms which the compounds of formula (la) or (Ib) are able to form. The latter can conveniently be obtained by treating the base form with such appropriate acids as inorganic acids, for example, hydrohalic acids, e.g. hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, 2-hydroxy-1,2,3 propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. Conversely the salt form can be converted by treatment with alkali into the free base form.

The compounds of formula (la) or (Ib) containing acidic protons may be converted into their therapeutically active non-toxic mētai or amine addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline mētai salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts vvith organic bases, e.g. primary, secondary and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-«-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline, the benzathine, A-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-l ,3-propanediol, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. Conversely the salt form can be converted by treatment vvith acid into the free acid form.

The term addition salt also comprises the hydrates and solvent addition forms vvhich the compounds of formula (la) or (Ib) are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.

The term “quatemary amine” as used hereinbefore defines the quatemary ammonium salts vvhich the compounds of formula (la) or (Ib) are able to form by reaction betvveen a basie nitrogen of a compound of formula (la) or (Ib) and an appropriate quatemizing

-8agent, such as, for example, an optionally substituted alkylhalide, arylhalide, alkylcarbonylhalide, arylcarbonylhalide, or arylalkylhalide, e.g. methyliodide or benzyliodide. Other reactants with good leaving groups may also be used, such as alkyl trifluoromethanesulfonates, alkyl methanesulfonates, and alkyl //-toluenesulfonates. A quatemary amine has a positiveiy charged nitrogen. Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate, acetate, triflate, sulfate, sulfonate. The counterion of choice can be introduced using ion exchange resins.

Compounds of either formula (ia) and (Ib) and some of the intermediate compounds invariably have at least two stereogenic centers in their structure which may lead to at least 4 stereochemically different struetures.

The term “stereochemically isomeric forms” as used hereinbefore or hereinafter dennes ali the possible stereoisomeric forms vvhich the compounds of formula (la) and (Ib), and their quatemary amines, 7V-oxides, addition salts or physiologically functional derivatives may possess. Unless otherwise mentioned or indicated, the Chemical designation of compounds denotes the mixture of ali possible stereochemically isomeric forms, said mixtures containing ali diastereomers and enantiomers of the basie molecular structure.

In particular, stereogenic centers may have the R- or S-configuration; substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or transconfiguration. Compounds eneompassing double bonds can have an E (entgegen) or Z (zusammen) -stereochemistiy at said double bond. The terms cis, trans, R, S, E and Z are vvell known to a person skilled in the art.

Stereochemically isomeric forms of the compounds of formula (la) and (Ib) are obviously intended to be embraced vvithin the scope of this invention.

Follovving CAS-nomenclature conventions, vvhen tvvo stereogenic centers of knovvn absolute configuration are present in a molecule, an 7? or 5 deseriptor is assigned (based on Cahn-Ingold-Prelog sequence rule) to the lovvest-numbered chiral center, the reference center. The configuration of the second stereogenic center is indicated using relative deseriptors [R*,R* ] or [7?*, 5*], vvhere R* is always specified as the reference center and [7? *7?*] indicates centers vvith the same chirality and [7?*,5*] indicates centers of unlike chirality. For example, if the lovvest-numbered chiral center in the molecule has an S configuration and the second center is 7?, the stereo deseriptor vvould be specified as S-fTž* 5*]. If “α” and “β” are used : the position of the highest priority

-9substituent on the asymmetric carbon atom in the ring system having the lovvest ring number, is arbitrarily always in the “α” position of the mean planē determined by the ring system. The position of the highest priority substituent on the other asymmetric carbon atom in the ring system relative to the position of the highest priority substituent on the reference atom is denominated “α”, if it is on the same side of the mean planē determined by the ring system, or “/3”, if it is on the other side of the mean planē determined by the ring system.

When a specific stereoisomeric form is indicated, this means that said form is 10 substantially free, i.e. associated with less than 50 %, preferably less than 20 %, more preferably less than 10%, even more preferably less than 5%, further preferably less than 2% and most preferably less than 1% of the other isomer(s). Thus, when a compound of formula (I) is for instance specified as (aS, pR), this means that the compound is.substantially free of the (aR, β S) isomer.

The compounds of either formula (la) and (Ib) may be synthesized in the form of racemic mixtures of enantiomers which can be separated from one another follovving art-known resolution procedures. The racemic compounds of either formula (la) and (Ib) may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An altemative manner of separating the enantiomeric forms of the compounds of either formula (la) and (Ib) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemieally isomeric forms of the appropriate starting materiāls, provided that the reaction occurs stereospecifīcally. Preferably if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materiāls.

The tautomeric forms of the compounds of either formula (la) and (Ib) are meant to comprise those compounds of either formula (la) and (Ib) vvherein e.g. an enol group is converted into a keto gToup (keto-enol tautomerism).

The A-oxide forms ofthe compounds according to either formula (la) and (Ib) are meant to comprise those compounds of either formula (la) and (Ib) vvherein one or several tertiary nitrogen atoms are oxidized to the so-called yV-oxide.

-10The compounds of formula (la) and (Ib) may be converted to the corresponding JV-oxide forms follovving art-known procedures for converting a trivalent nitrogen into its #-oxide form. Said jV-oxidation reaction may generally be canried out by reacting the starting material of formula (la) and (Ib) vvith an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali mētai or earth alkaline mētai peroxides, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid,

e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. t.butyl hydro-peroxide. Suitable solvents are, for example, vvater, lovver alcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.

The invention also comprises derivative compounds (usually called “pro-drugs”) of the pharmacologically-active compounds according to the invention, vvhich are degraded in vivo to yield the compounds according to the invention. Pro-drugs are usually (but not always) of lovver potency at the target receptor than the compounds to vvhich they are degraded. Pro-drugs are particularly useiul vvhen the desired compound has Chemical or physical properties that make its administration difficult or inefficient, For example, the desired compound may be only poorly soluble, it may be poorly transported across the mucosal epithelium, or it may have an undesirably short plasma half-life. Further discussion on pro-drugs may be found in Stella, V. J. et al., “Prodrugs”, DrugDelivery

Systems, 1985, pp. 112-176, aad Drugs, 1985, 29, pp. 455-473.

Pro-drug forms ofthe pharmacologically-active compounds according to the invention vvill generally be compounds according to either formula (la) and (Ib), the pharmaceutically acceptable acid or base addition salts thereof, the quatemaiy amines thereof, the stereochemically isomeric forms thereof, the tautomeric forms thereof and the 7V-oxide forms thereof, having an acid group vvhich is esterified or amidated. Included in such esterified acid groups are groups of the formula -COOR\ vvhere R* is a C,_6alkyl, phenyl, benzyl or one of the follovving groups :

Amidated groups include groups of the formula - CONR^yR^z, wherein R^y is H, Ci-6alkyl, phenyl or benzyl and R^z is -OH, H, Ci.6alkyl, phenyl or benzyl.

Compounds according to the invention having an amino group may be derivatised with a ketone or an aldehyde such as foimaldehyde to form a Mannich base. This base vvill hydrolyze vvith first order kinetics in aqueous solution.

Whenever used herein, the term compounds of formula (la) or (Ib) is meant to also 10 include their pharmaceutically acceptable acid or base addition salts, their quatemary amīnes, their 7V-oxide forms, their tautomeric forms or their stereochemically isomeric forms. Of special interesi are those compounds of formula (la) or (Ib) vvhich are stereochemically pure.

A first interesting embodiment of the present invention relates to the use as defined hereinbefore of compounds of formulā (la) or (Ib), vvherein the compound of formula (la) or (Ib) is (R®)r (R')p

R ,Ν

Υ-,5 (Ib) a pharmaceutically acceptabie acid or base addition salt thereof, a A-oxide thereof, a tautomeric form thereof or a stereochemically isomeric form thereof vvherein R¹ is hydrogen, halo, haloalkyl, cyano, hydroxy, Ar, Het, alkyl, alkyloxy, alkylthio, alkyloxyalkyl, alkylthioalkyl, Ar-alkyl or di(Ar)alkyl;

p is an integer equal to 1, 2, 3 or 4 ;

R² is hydrogen, hydroxy, mercapto, alkyloxy, alkyloxyalkyloxy, alkylthio, ' Y mono or di(alkyl)amino or a radical of formula vvherein Y is

CH₂, O, S,NH orN-alkyl;

R³ is alkyl, Ar, Ar-alkyl, Het or Het-alkyl;

q is an integer equal to zero, 1, 2, 3 or 4 ;

R⁴ and R⁵ each independently are hydrogen, alkyl or benzyl; or

R⁴ and R⁵ together and including the N to vvhich they are attached may form a radical selected from the group of pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, 2-imidazolinyl, 2-pyrazolinyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, piperazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, morpholinyl and thiomorpholinyl, each of said ring systems optionally substituted vvith alkyl, halo, haloalkyl, hydroxy, alkyloxy, amino, mono- or dialkylamino, alkylthio, alkyloxyalkyl, alkylthioalkyl and pyrimidinyl;

R⁶ is hydrogen, halo, haloalkyl, hydroxy, Ar, alkyl, alkyloxy, alkylthio, alkyloxyalkyl, alkylthioalkyl, Ar-alkyl or di(Ar)alkyl; or tvvo viciņai R⁶ radicals may be taken together to form a bivalent radical of formula

-CH=CH-CH=CH-;

r is an integer equal to 1, 2, 3, 4 or 5 ;

is hydrogen, alkyl, Ar or Het;

-13R is hydrogen or alkyl;

R⁹ is oxo ; or

R^s and R⁹ together form the radical =N-CH=CH-;

alkyl is a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms ; or is a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms; or is a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms attached to a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms ; vvherein each carbon atom can be optionally substituted vvith halo, hydroxy, alkyloxy or oxo ;

Het is a monocyclic heterocycle selected from the group of V-phenoxypiperidinyl, piperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; or a bicyclic heterocycle selected from the group of quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2,3dihydrobenzo[l,4]dioxinyl or benzo[l,3]dioxolyl; each monocyclic and bicyclic heterocycle may optionally be substituted vvith 1,2 or 3 substituents selected from the group of halo, hydroxy, alkyl, alkyloxy, or Ar-carbonyl;

halo is a substituent selected from the group of fluoro, chloro, bromo and iodo; and haloalkyl is a straight or branched saturated hydrocarbon radical having from 1 to carbon atoms or a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms, vvherein one or more carbon atoms are substituted vvith one or more halo-atoms.

A second interesting embodiment of the present invention relates to the use as defined hereinbefore of compounds of formula (la) or (lb) or any subgroup thereof as mentioned hereinbefore as interesting embodiment vvherein

R¹ is hydrogen, halo, cyano, Ar, Het, alkyl, and alkyloxy ; is an integer equal to 1, 2, 3 or 4 ; in particular 1 or 2;

-14R² is hydrogen, hydroxy, alkyloxy, alkyloxyalkyloxy, alkylthio or a radical of

formula wherein Y is 0 ;

R³ is alkyl, Ar, Ar-alkyl or Het;

q is an integer equal to zero, 1, 2, or 3 ;

R⁴ and R⁵ each independently are hydrogen, alkyl or benzyl; or

R⁴ and R⁵ together and including the N to vvhich they are attached may form a radical selected from the group of pyrrolidinyl, imidazolyl, triazolyl, piperidinyl, piperāzinyl, pyrazinyl, morpholinyl and thiomorpholinyl, each ring system optionally substituted vvith alkyl or pyrimidinyl;

R⁶ is hydrogen, halo or alkyl; or tvvo viciņai R⁶ radicals may be taken together to form a bivalent radical of formula -CH=CH-CH=CH-;

r is an integer equal to 1 ;

R⁷ is hydrogen;

R⁸ is hydrogen or alkyl;

R⁹ is oxo ; or

R⁸ and R⁹ together form the radical =N-CH=CH-;

alkyl is a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms ; or is a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms ; or is a a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms attached to a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms ; vvherein each carbon atom can be optionally substituted vvith halo or hydroxy ;

Ar is a homocycle selected from the group of phenyl, naphthyl, acenaphthyl, tetrahydronaphthyl, each homocycle optionally substituted vvith 1, 2 or 3 substituents, each substituent independently selected from the group of halo, haloalkyl, cyano, alkyloxy and morpholinyl;

Het is a monocyclic heterocycle selected from the group of A-phenoxypiperidinyl, piperidinyl, furanyl, thienyl, pyridinyl, pyrimidinyl; or a bicyclic heterocycle selected from the group ofbenzothienyl, 2,3-dihydrobenzo[l,4]dioxinyl or benzo[l,3]dioxolyl; each monocyclic and bicyclic heterocycle may optionally be substituted vvith 1, 2 or 3 alkyl or Ar-carbonyl substituents ; and halo is a substituent selected from the group of fluoro, chloro and bromo.

-15In a third interesting embodiment the compounds of formula (la) or (Ib) or any subgroup thereof as mentioned hereinbefore as interesting embodiment are those compounds according to either formula (la) and (Ib) wherein R¹ is hydrogen, halo, Ar, alkyl or alkyloxy; preferably, R¹ is halo; more preferably, R¹ is bromo.

In a fourth interesting embodiment the compounds of formula (la) or (Ib) or any subgroup thereof as mentioned hereinbefore as interesting embodiment are those compounds according to either formula (la) and (Ib) vvherein p is equal to 1 and R¹ is different from hydrogen.

In a fifth interesting embodiment the compounds of formula (la) or (Ib) or any subgroup thereof as mentioned hereinbefore as interesting embodiment are those compounds according to either formula (la) and (Ib) vvherein R² is hydrogen, alkyloxy or alkyIthio; preferably, R² is alkyloxy, in particular CMalkyloxy; more preferably, R² is methyloxy.

CMalkyl is a straight or branched saturated hydrocarbon radical having from 1 to 4 carbon atoms such as for example methyl, ethyl, propyl, 2-methyl-ethyl and the like.

In a sixth interesting embodiment the compounds of formula (la) or (Ib) or any 20 subgroup thereof as mentioned hereinbefore as interesting embodiment are those compounds according to either formula (la) and (Ib) vvherein R³ is naphthyl, phenyl or thienyl, each optionally substituted vvith 1 or 2 substituents, that substituent preferably being a halo or haloalkyl, most preferably being a halo; preferably, R³ is naphthyl or phenyl, each optionally substituted vvith halo, preferably 3-fluoro; more preferably, R³ is naphthyl or phenyl; most preferably, R³ is naphthyl.

In a seventh interesting embodiment the compounds of formula (la) or (Ib) or any subgroup thereof as mentioned hereinbefore as interesting embodiment are those compounds according to either formula (la) and (Ib) vvherein q is equal to zero, 1 or 2;

preferably, q is equal to 1.

In an eighth interesting embodiment the compounds of formula (la) or (Ib) or any subgroup thereof as mentioned hereinbefore as interesting embodiment are those compounds according to either formula (la) and (Ib) vvherein R⁴ and R⁵ each independently are hydrogen or alkyl, in particular hydrogen or C)4alkyl, more in particular Ci_4alkyl; preferably hydrogen, methyl or ethyl; most preferably methyl.

-16Ci-4alkyl is a straight or branched saturated hydrocarbon radical having from 1 to 4 carbon atoms such as for example methyl, ethyl, propyl, 2-methyl-ethyl and the like.

In a ninth interesting embodiment the compounds of formula (la) or (Ib) or any subgroup thereof as mentioned hereinbefore as interesting embodiment are those compounds according to either formula (la) and (Ib) vvherein R⁴ and R⁵ together and including the N to vvhich they are attached form a radical selected from the group of imidazolyl, triazolyl, piperidinyl, piperazinyl and thiomorpholinyl, optionally substituted vvith alkyl, halo, haloalkyl, hydroxy, alkyloxy, alkylthio, alkyloxyalkyl or alkylthioalkyl, preferably substituted vvith alkyl, most preferably substituted vvith methyl or ethyl.

In a tenth interesting embodiment the compounds of formula (la) or (Ib) or any subgroup thereof as mentioned hereinbefore as interesting embodiment are those compounds according to either formula (la) and (Ib) vvherein R⁶ is hydrogen, alkyl or halo; preferably, R⁶ is hydrogen.

In an eleventh interesting embodiment the compounds of formula (la) or (Ib) or any subgroup thereof as mentioned hereinbefore as interesting embodiment are those compounds according to either formula (la) and (Ib) vvherein r is 1 or 2.

In a tvvelfth interesting embodiment the compounds of formula (la) or (Ib) or any subgroup thereof as mentioned hereinbefore as interesting embodiment are those compounds according to either formula (la) and (Ib) vvherein R⁷ is hydrogen or methyl; preferably R⁷ is hydrogen.

In a thirteenth interesting embodiment the compounds of formula (la) or (Ib) or any subgroup thereof as mentioned hereinbefore as interesting embodiment are those compounds according to either formula (la) and (Ib) vvherein, for compounds according to Formula (Ib) only, R⁸ is alkyl, preferably methyl, and R⁹ is oxygen.

In a fourteenth interesting embodiment the compounds of formula (la) or (Ib) or any subgroup thereof as mentioned hereinbefore as interesting embodiment are those compounds according to either formula (la) and (Ib) vvherein the compound is a compound according to formula (la), a pharmaceutically acceptable acid or base addition salt thereof, a quatemary amine thereof, a 7V-oxide thereof, a tautomeric form thereof or a stereochemically isomeric form thereof.

-17A fifteenth interesting embodiment of the compounds of formula (la) or (Ib) are the compounds according to formula (la), the pharmaceutically acceptable acid or base addition salts thereof, the quatemary amines thereof, the stereochemically isomeric forms thereof, the tautomeric forms thereof or the JV-oxide forms thereof, in vvhich R¹ is hydrogen, halo, Ar, alkyl or alkyloxy; p = 1; R² is hydrogen, alkyloxy or alkylthio; R³is naphthyl, phenyl or thienyl, each optionally substituted vvith 1 or 2 substituents selected from the group of halo and haloalkyl; q = 0, 1, 2 or 3; R⁴ and R⁵ each independently are hydrogen or alkyl or R⁴ and R⁵ together and including the N to vvhich they are attached form a radical selected from the group of imidazolyl, triazolyl, piperidinyl, piperazinyl and thiomorpholinyl; R⁶ is hydrogen, alkyl or halo; r is equal to 1 and R⁷ is hydrogen.

A sixteenth interesting embodiment of the compounds of formula (la) or (Ib) are the compounds of formula (la) or (Ib) or any subgroup thereof as mentioned hereinbefore as interesting embodiment or the pharmaceutically acceptable acid or base addition salts thereof.

A seventeenth interesting embodiment of the compounds of formula (la) or (Ib) are the compounds of formula (la) or (Ib) or any subgroup thereof as mentioned hereinbefore as interesting embodiment or the quatemary amines thereof.

An eighteenth interesting embodiment of the compounds of formula (la) or (Ib) are the compounds of formula (la) or (Ib) or any subgroup thereof as mentioned hereinbefore as interesting embodiment or the N-oxides thereof.

A nineteenth interesting embodiment of the compounds of formula (la) or (Ib) are the compounds of formula (la) or (Ib) or any subgroup thereof as mentioned hereinbefore as interesting embodiment or the stereochemically isomeric forms thereof.

A tvventieth interesting embodiment of the compounds of formula (la) or (Ib) are the compounds of formula (la) or (Ib) or any subgroup thereof as mentioned hereinbefore as interesting embodiment.

Preferably, in the compounds of formula (la) and (Ib) or any subgroup thereof as mentioned hereinbefore as interesting embodiment, the term “alkyl” represents Ci.

6alkyl vvherein Ci_6alkyl is a straight or branched saturated hydrocarbon radical having

-18from 1 to 6 carbon atoms such as for example methyl, ethyl, propyl, 2-methyl-ethyl, pentyl, hexyl and the like.

Preferably, in the compounds of formula (la) and (Ib) or any subgroup thereof as 5 mentioned hereinbefore as interesting embodiment, the term “haloalkyl” represents polyhaloCi-6alkyl vvhich is defined as mono- or polyhalosubstituted Ci^alkyl, for example, methyl vvith one or more fluoro atoms, for example, difluoromethyl or trifluoromethyl, I,l-difluoro-ethyl and the like. In case more than one halogen atoms are attached to an alkyl group vvithin the definition of polyhaloCi^alkyl, they may be the same or different. Ci^alkyl is a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms such as for example methyl, ethyl, propyl, 2-methylethyl, pentyl, hexyl and the like.

Preferably, the compound is selected from :

o l-(6-bromo-2-methoxy-quinolin-3-yl)-2-(3,5-difluoro-phenyl)-4-dimethylamino-lphenyl-butan-2-ol;

o l-(6-bromo-2-methoxy-quinolin-3-yl)-4-dimethylamino-2-naphthalen-l-yl-lphenyl-butan-2-ol corresponding to 6-bromo-a-[2-(dimethylamino)ethyl]-2methoxy-a-1 -naphthalenyl-3-phenyl-3-quinolineethanol;

o l-(6-bromo-2-methoxy-qumolin-3-yl)-2-(2,5-difluoro-phenyl)-4-dimethylamino-lphenyl-butan-2-ol;

ο 1 -(6-bromo-2-methoxy-quinolin-3-yl)-2-(2,3-difluoro-phenyl)-4-dimethylamino-1 phenyl-butan-2-ol;

ο 1 -(6-bromo-2-methoxy-quinolin-3-yl)-4-dimethylamino-2-(2-fluoro-phenyl)-1 25 phenyl-butan-2-ol;

ο 1 -(6-bromo-2-methoxy-quinolin-3-yl)-4-dimethylamino-2-naphthalen-1 -yl-1 -ptolyl-butan-2-ol;

ο 1 -(6-bromo-2-methoxy-quinolin-3-yl)-4-methylamino-2-naphthalen-1 -yl-1 -phenylbutan-2-ol;

ο 1 -(6-bromo-2-methoxy-quinolin-3-yl)-4-dimethylamino-2-(3 -fluoro-phenyl)-1 phenyl-butan-2-ol; and o l-(6-bromo-2-methoxy-quinolin-3-yl)-4-dimethylamino-2-phenyl-l-phenyl-butan2-ol;

a pharmaceutically acceptable acid or base addition salt thereof, a 7f-oxide thereof, a tautomeric form thereof or a stereochemically isomeric form thereof.

More preferably, the compound is

-19o 1 -(6-bromo-2-methoxy-quinolin-3-yl)-2-(2,3-difluoro-phenyl)-4-dimethylamino-1 phenyl-butan-2-ol; or ο 1 -(6-bromo-2-methoxy-quinolin-3 -yl)-4-dimethylamino-2-naphthalen-1 -yl-1 phenyI-butan-2-ol corresponding to 6-bromo-a-[2-(dimethylamino)ethyl]-25 methoxy-a-l-naphthalenyl-3-phenyl-3-qumolineethanol;

a pbarmaceutically acceptable acid or base addition salt thereof, a A-oxide thereof, a tautomeric form thereof or a stereochemically isomeric form thereof.

Even more preferably, the compound is l-(6-bromo-2-methoxy-quinolin-3-yl)-410 dimethylamino-2-naphthalen-1 -yl-1 -pbenyl-butan-2-ol, a pharmaceutically acceptable acid or base addition salt thereof, a 7V-oxide thereof, or a stereochemically isomeric form thereof.

An alternative Chemical name for l-(6-bromo-2-methoxy-quinolin-3-yl)-415 dimethylamino-2-naphthalen-1 -yl-1 -phenyl-butan-2-ol is 6-bromo-a-[2(dimethylamino)ethyl]-2-methoxy-a-l-naphthalenyl-p-phenyl-3-quinolineethanol.

Said compound can also be represented as follovvs :

Further preferably, the compound is one of the follovving :

6-bromo-a-[2-(dimethylamino)ethyl]-2-methoxy-a-l-naphthalenyl-3-phenyl-3quinolineethanol, or a pharmaceutically acceptable acid addition salt thereof; or 6-bromo-a-[2-(dimethylammo)ethyl]-2-methoxy-cc-l-naphthalenyl-3-phenyl-3quinolineethanol, or a stereochemically isomeric form thereof; or

6-bromo-a-[2-(dimethylamino)ethyl]-2-methoxy-oc-l-naphthalenyl-P-phenyl-3quinolineethanol, or a A^Loxide form thereof; or a mixture, in particular a racemic mixture, of (aS, 3R)-6-bromo-a-[2(dimethylamino)ethyl]-2-methoxy-a-1 -naphthalenyl^-phenyl-3-quinolineethanol and (aR, β S)-6-bromo-a-[2-(dimethylamino)ethyl]-2-methoxy-a-1 -naphthalenyl-$-20phenyl-3-quinolineethanol, or a pharmaceutically acceptable acid addition salt thereof, or a stereochemically isomeric forms thereof; i.e. compound 14 (diastereoisomer A); or (aS, 3R)-6-bromo-a-[2-(dimethylamino)ethyl]-2-methoxy-a-1 -naphthalenyl-p-phenyl3-quinolineethanol, i.e. compound 12, or a pharmaceutically acceptable acid addition salt thereof; or (aS, 3R)-6-bromo-a-[2-(dimethylamino)ethyl]-2-methoxy-a-l-naphthalenyl-3-phenyl3-quinolineethanol, i.e. compound 12.

The most preferred compound is (aS, 3R)-6-bromo-a-[2-(dimethylamino)ethyl]-210 methoxy-a-l-naphthalenyl-3-phenyl-3-quinolineethanol which corresponds to (1R,2S)1 -(6-bromo-2-methoxy-quinolin-3-yl)-4-dimethylamino-2-naphthalen-1 -yl-1 -phenylbutan-2-οΙ. Said compound can also be represented as follovvs :

Another interesting group of compounds is the following : compounds 12, 71,174, 75, 172, 79 and 125 as described hereinafter in Tables 1 to 6; in particular compounds 12, 71, 174, 75, 172 and 79 or compounds 12, 71, 75, 172 and 125; more in particular compounds 12, 71,174 and 75 or compounds 12, 71, 75 and 172; even more in particular compounds 12, 71 and 174 or compounds 12, 71 and 75; a pharmaceutically acceptable acid or base addition salt thereof, a JV-oxide thereof, a tautomeric form thereof or a stereochemically isomeric form thereof.

The compounds of formula (la) and (Ib) can be prepared according to the methods described in WO 2004/011436, which is incorporated herein by reference.

In general, the compounds according to the invention can be prepared by a succession of steps, each of vvhich is knovvn to the skilled person.

In particular, the compounds according to formula (la) can be prepared by reacting an intermediate compound of formula (Π) vvith an intermediate compound of formula (III) according to the follovving reaction scheme (1):

-21Scheme 1

using BuLi in a mixture of diisopropyl amine and tetrahydrofuran, and v/herein ali variables are defined as in formula (la). Stirring may enhance the rāte of the reaction. The reaction may conveniently be carried out at a temperature ranging betvveen -20 and -70 °C.

The same reaction procedure can be used.to synthesize compounds of formula (Ib).

The starting materiāls and the intennediate compounds of formula (Π) and (ΙΠ) are compounds that are either commercially available or may be prepared according to conventional reaction procedures generally knovvn in the art. For example, intennediate compounds of formula (Π-a) may be prepared according to the follovving reaction scheme (2):

Scheme 2

(Il-a)

-22vvherein ali variables are defined as in formula (la). Reaction scheme (2) comprises step (a) in vvhich an appropriately substituted aniline is reacted vvith an appropriate acylchloride such as 3-phenylpropionyl chloride, 3-fluorobenzenepropanoyl chloride or /?-chlorobenzenepropanoyl chloride, in the presence of a suitable base, such as triethylamine and a suitable reaction-inert soivent, such as methylene chloride or ethylene dichloride. The reaction may conveniently be carried out at a temperature ranging betvveen room temperature and reflux temperature. In a next step (b) the adduct obtained in step (a) is reacted vvith phosphoryl chloride (POCI3) in the presence of jV,7V-dimethylformamide (Vilsmeier-Haack formylation follovved by cyclization).

The reaction may conveniently be carried out at a temperature ranging betvveen room temperature and reflux temperature. In a next step (c) a specific R²-group, vvherein R²is for example an Cj^alkyloxy or Ci^alkylthio radical is introduced by reacting the intermediate compound obtained in step (b) vvith a compound H-X-Ci^alkyl vvherein X is S or 0.

Intermediate compounds according to formula (Il-b) may be prepared according to the follovving reaction scheme (3), vvherein in a first step (a) a substituted indole-2,3-dione is reacted vvith a substituted 3-phenylpropionaldehyde in the presence of a suitable base such as sodium hydroxide (Pfitzinger reaction), after vvhich the resulting carboxylic acid compound is decarboxylated in a.next step (b) at high temperature in the presence of a suitable reaction-inert soivent such as diphenylether.

Scheme 3

(Il-b)

-23It is evident that in the foregoing and in the follovving reactions, the reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally knovvn in the art, such as extraction, crystallization and chromatography. It is further evident that reaction products that exist in more than one enantiomeric form, may be isolated from their mixture by knovvn techniques, in particular preparative chromatography, such as preparative HPLC. Typically, compounds of formula (I) may be separated into their isomeric forms.

The intermediate compounds of formula (ΙΠ) are compounds that are either 10 commercially available or may be prepared according to conventional reaction procedures generally knovvn in the art. For example, intermediate compounds of formula (ΠΙ-a) in vvhich R³ is Ar substituted vvith s substituents R¹⁰, vvherein each R¹⁰is independently selected from the group of hydroxy, halo, cyano, nitro, amino, monoor di(Ci^alkyl)amino, Ci^alkyl, polyhaloCi^alkyl, Ci^alkyloxy, polyhaloC]^alkyloxy, carboxyl, Cļ^alkyloxycarbonyl, aminocarbonyl, morpholinyl and mono- or di(Ci_ 6alkyl)aminocarbonyl and s is an integer equal to zero, 1, 2 or 3, may be prepared according to the follovving reaction scheme (4):

Scheme 4 (R¹⁰)_s (R

10x

Ar

Cl (CH₂), (a) (CH₂)_qCl (b) (R¹⁰!

(CH₂)_q\ (lll-a)

Reaction scheme (4) comprises step (a) in vvhich an appropriately substituted Ar, in particular an appropriately substituted phenyl, is reacted by Friedel-Craft reaction vvith an appropriate acylchloride such as 3-chloropropionyl chloride or 4-chlorobutyryl chloride, in the presence of a suitable Levvis acid, such as for example AlCķ, FeCL, SnCfi, TiCfi or ZnCfi and a suitable reaction-inert solvent, such as methylene chloride or ethylene dichloride. The reaction may conveniently be carried out at a temperature ranging betvveen room temperature and reflux temperature. In a next step (b) an amino group (-NR⁴R⁵) is introduced by reacting the intermediate compound obtained in step (a) vvith an appropriate primary or secondary amine.

As for the interpretation of the present invention, latent TB, dormant TB or persistent TB are the same (TB stands for tuberculosis).

-24As already stated above, the compounds of formula (la) and (Ib) can be used to treat latent TB. The exact dosage and frequency of administration of the present compounds depends on the particular compound of formula (la) and (Ib) used, the particular condition being treated, the severity of the condition being treated, the age, vveight, gender, diet, time of administration and general physical condition of the particular patient, the mode of administration as vveil as other medication the individual may be taking, as is vveil knovvn to those skilled in the art. Furthermore, it is evident that the effective daily amount may be lovvered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention.

The compounds of the present invention may be administered in a pharmaceutically acceptable form optionally in a pharmaceutically acceptable carrier.

The pharmaceutical compositions may have various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited ali compositions usually employed for systemically administering drugs. To prepare the pharmaceutical compositions, an effective amount of the particular compounds, optionally in addition salt form, as the active ingredient is combined in intimate admixture vvith a pharmaceutically acceptable carrier, vvhich carrier may take a vvide variety of forms depending on the form of preparation desired for administration.

These pharmaceutical compositions are desirable in unitaiy dosage form suitable, in particular, for administration orally or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as, for example, vvater, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and Solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating aģents and the like in the case of povvders, pilis, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral unit dosage forms in vvhich case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier vvill usually comprise sterile vvater, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable Solutions, for example, may be prepared in vvhich the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in vvhich case appropriate liquid carriers, suspending aģents and the like may be employed. Also

-25included are solid form preparations vvhich are intended to be converted, shortly before use, to liquid form preparations.

Depending on the mode of administration, the pharmaceutical composition vvill 5 preferably comprise from 0.05 to 99 % by vveight, more preferably from 0.1 to 70 % by vveight ofthe active ingredient, and, from 1 to 99.95 % by vveight, more preferably from 30 to 99.9 vveight % of a pharmaceutically acceptable carrier, ali percentages being based on the total composition.

The pharmaceutical composition may additionally contain various other ingredients knovvn in the art, for example, a lubricant, stabilising aģent, buffering aģent, emulsifying aģent, viscosity-regulating aģent, surfactant, preservative, flavouring or coiorant.

It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and unifonnity of dosage. Unit dosage form as used herein refers to physically discrete units suitabie as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to producē the desired therapeutic effect in association vvith the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pilis, povvder packets, vvafers, suppositories, injectable Solutions or suspensions and the like, and segregated multiples thereof.

The daily dosage of the compound according to the invention vvill, of course, vary vvith the compound employed, the mode of administration, the treatment desired and the mycobacterial disease indicated. Hovvever, in general, satisfaetory results vvill be obtained vvhen the compound according to the invention is administered at a daily dosage not exceeding 1 or 2 gram, e.g. in the range from 10 to 50 mg/kg body vveight.

EXPERIMENTAL PART

As already stated above, the compounds of formula (la) and (Ib) and their preparation is described in WO 2004/011436, vvhich is incorporated herein by reference.

Of some compounds the absolute stereochemical configuration of the stereogenic carbon atom(s) therein vvas not experimentally determined. In those cases the stereochemically isomeric form vvhich vvas first isolated is designated as “A” and the second as “B”, vvithout further reference to the actual stereochemical configuration. Hovvever, said “A” and “B” isomeric forms can be unambiguously characterized by a

-26person skilled in the art, using art-known methods such as, for example, X-ray diffraction.

In case “A” and “B” are stereoisomeric mixtures, they can be further separated whereby the respective first fractions isolated are designated “Al” respectively “Bl” and the second as “A2” respectively “B2”, vvithout further reference to the actual stereochemical configuration. Hovvever, said “Al, A2” and “Bl, B2” isomeric forms can be unambiguously characterized by a person skilled in the art, using art-knovvn methods such as, for example, X-ray diffraction.

The present compounds (see Tables 1 to 6) are numbered in conformity vvith the compounds of WO 2004/011436 and can be prepared according to the methods described in WO 2004/011436. The Ex. Nr. in the belovv Tables refer to the Example numbers of WO 2004/011436 indicating according to vvhich procedure the compounds can be prepared.

In particular, the preparation of compounds 12,13, 12a, 13a, 14 and 15 are described belovv in detail.

Hereinafter, “DMF” is defined as #,X-dimethylformamide, “THF” is defined as tetrahydrofuran, “DIPE” is defined as diisopropylether.

Preparation of the intermediate compounds

Example Al

Preparation of intermediate compound 1

Benzenepropanoylchloride (0.488 mol) vvas added dropvvise at room temperature to a solution of 4-bromobenzenamine (0.407 mol) inEt₃N (70ml) and CH₂C1₂ (700ml) and the mixture vvas stirred at room temperature overnight. The mixture vvas poured out into vvater and concentrated NH4OH, and extracted vvith CH₂C1₂. The organic layer vvas dried (MgSO₄), filtered, and the solvent vvas evaporated . The residue vvas crystallized from diethyl ether . The residue (119.67g) vvas taken up in CH₂C1₂ and vvashed vvith HCI IN . The organic layer vvas dried (MgSO₄), filtered, and the solvent vvas evaporated. Yield: 107.67g of intermediate compound 1.

-27Example A2

Preparation of intermediate compound 2

Br

The reaction was carried out tvvice . POCh (1.225 mol) vvas added dropvvise at 10°C to 7V,7V-dimethylformamide (DMF) (0.525 mol). Then intermediate compound 1 (prepared according Al) (0.175 mol) vvas added at room temperature . The mixture vvas stirred ovemight at 80°C, poured out on ice and extracted vvith CH₂C1₂. The organic layer vvas dried (MgSCb), filtered, and the solvent vvas evaporated . The product vvas used vvithout further purification. Yield : 77.62g of intermediate compound 2 (67%).

Example A3

Preparation of intermediate compound 3

BrA mixture of intermediate compound 2 (prepared according to A2) (0.233 mol) in CHsONa (30%) in methanol (222.32 ml) and methanol (776ml) vvas stirred and refluxed ovemight, then poured out on ice and extracted vvith CH₂C1₂ . The organic layer vvas separated, dried (MgSO₄), filtered and the solvent vvas evaporated . The residue vvas purified by column chromatography over silica gel (eluent:

CH₂Cl₂/cyclohexane 20/80 and then 100/0; 20-45pm). The pure fractions vvere collected and the solvent vvas evaporated . Yield : 25g of intermediate compound 3 (Yield=33%; mp.84°C) as a vvhite povvder .

Preparation of final compounds 12, 13, 12a, 13a. 14 and 15

Preparation of final compounds 12,

13, 12a, 13a, 14 and 15

[alpha]_D ²⁰ = -42.56 (e=0.336g/100ml in DMF)

[alpha]_D ²⁰ = +167.60 (c=0.472g/100ml in DMF)

[alpha]_D ²⁰ =+43.55 (c=0.349g/100ml in DMF) nBuLi 1.6M (0.05 mol) vvas added slovvly at -20°C under N2 flovv to a solution of A-(l-methylethyl)-2-propanamine (0.05 mol) in tetrahydrofuran (THF) (80ml). The mixture vvas stirred at -20°C for 15 minūtes, then cooled to -70°C . A solution of intermediate compound 3 (prepared according to A3 described above) (0.046 mol) in THF (150ml) vvas added slovvly . The mixture vvas stirred at -70°C for 30 minūtes . A solution of 0.055 mol of3-(dimethylamino)-l-(l-naphthyl)-l-propanone in THF (120ml) vvas added slowly . The mixture vvas stirred at -70°C for 3 hours, hydrolyzed at -30°C vvith ice vvater and extracted vvith EtOAc . The organic layer vvas separated, dried (MgSCA), filtered, and the solvent vvas evaporated . The residue (29g) vvas purified by column chromatography over silica gel (eluent: CH2CI2/CH3OH/NH4OH; 99.5/0.5/0.1; 15-35pm). Tvvo fractions vvere collected and the solvent vvas evaporated,

-29yielding 3g of fraction 1 and 4.4g of fraction 2 . Fraction 1 and 2 vvere crystallized separately from DIPE . The precipitate vvas filtered off and dried, yielding 2.2g of diastereoisomer A, i.e. final compound 14 (Yield: 9%; mp.210°C) as a vvhite solid and 4g of diastereoisomer B, i.e. final compound 15 (Yield: 16%; mp.244°C) as a vvhite solid . To obtain the corresponding enantiomers, diastereoisomer A (final compound 14) vvas purified by chiral chromatography over silica gel (chiralpack AD) (eluent: hexane/EtOH; 99.95/0.05). Tvvo fractions vvere collected and the solvent vvas evaporated . Yield: 0.233g of enantiomer Al (final compound 12) (mp. 118°C, [a]_D ²⁰= -166.98° (c = 0.505 g/100 ml in DMF)) as a vvhite solid and 0.287g of enantiomer A2 (final compound 13) (mp. 120°C, [ot]_D ²⁰ = +167.60⁰ (c = 0.472 g/100 ml in DMF)) as a vvhite solid. Enantiomer Al vvas crystallised from EtOH to give a vvhite solid: mp. 184°C, [cc]d²⁰ = -188.71°(c= 0.621 g/lOOml in DMF). Crystallization of enantiomer A2 from EtOH gavē a solid vvith mp. of 175°C.

0.2g of diastereoisomer B (final compound 15) vvas purified by chiral chromatography over silica gel (chiralpack AD) (eluent: EtOH/iPrOH/jV-ethyl-ethanamine; 50/50/0.1). Tvvo fractions vvere collected and the solvent vvas evaporated . Yield: 78.2mg of enantiomer Bl and 78.8mg of enantiomer B2. Enantiomer Bl vvas purified by column chromatography over silica gel (eluent: CH2CI2/CH3OH/NH4OH; 99/1/0.1; 15-40pm). One fraction vvas collected and the solvent vvas evaporated . Yield: 57mg of enantiomer Bl (final compound 12ā) ([a]o²° = -42.56⁰ (c = 0.336 g/100 ml in DMF)). Enantiomer B2 vvas purified by column chromatography over silica gel (eluent: CH2CI2/CH3OH/NH4OH; 99/1/0.1; 15-40um). One fraction vvas collected and the solvent vvas evaporated . Yield: 53mg of enantiomer B2 (final compound 13a) ([oc]d²° = + 43.55⁰ (c = 0.349 g/100 ml in DMF)).

Tables 1 to 6 list compounds of formula (la) and (Ib).

-30Table 1 :

R⁶

Comp. nr	Ex. nr.	R¹	R²	R³	R⁶	Stereochemistry and melting points
1	Bl	Br	och₃	phenyl	H	(Al); 194°C
2	Bl	Br	och₃	phenyl	H	(A2); 191 °C
3	Bl	Br	och₃	phenyl	H	(A); 200°C
4	Bl	Br	och₃	phenyl	H	(B); 190°C
16	Bl	Br	och₃	4-chlorophenyl	H	(A); 200°C
17	Bl	Br	och₃	4-chlorophenyl	H	(B); 190°C
20	Bl	Br	och₃	2-thienyl	H	(A); 96°C
21	Bl	Br	och₃	2-thienyl	H	(B); 176°C
22	Bl	ch₃	och₃	phenyl	H	(A); 148°C
23	Bl	ch₃	och₃	phenyl	H	(B); 165°C
24	Bl	Br	och₃	3-thienyl	H	(A); 162°C
25	Bl	Br	och₃	3-thienyl	H	(B); 160°C
26	Bl	phenyl	och₃	phenyl	H	(A); 174°C
27	Bl	phenyl	och₃	phenyl	H	(B); 192°C
28	Bl	F	och₃	phenyl	H	(A); 190°C
29	Bl	F	och₃	phenyl	H	(B); 166°C
30	Bl	Cl	och₃	phenyl	H	(A); 170°C
31	Bl	Cl	och₃	phenyl	H	(B); 18I°C
32	Bl	Br	sch₃	phenyl	H	(A); 208°C
33	Bl	Br	sch₃	phenyl	H	(B); 196°C
34	Bl	och₃	och₃	phenyl	H	(A); 165°C
35	Bl	och₃	och₃	phenyl	H	(B); 165°C
36	Bl	Br	och₃	phenyl	Cl	(A); 197°C
37	Bl	Br	OCHj	phenyl	Cl	(B); 221°C
38	B9	Br	och₃	3-fluorophenyl	H	(A); 198°C
39	B9	Br	och₃	3-fluorophenyl	H	(B); 207°C

Comp. m	Ex. nr.	R¹	R²	R³	R⁶	Stereochemistrv and melting points
108	B9	Br	och₃	3-fluorophenyl	H	(Al); 160°C
109	B9	Br	och₃	3-fluorophenyl	H	(A2); 156°C
40	Bl	H	och₃	phenyl	H	(A); 152°C
41	Bl	H	och₃	phenyl	H	(B); 160°C
42	Bl	H	och₃	ch₃	H	(A); 140°C
43	Bl	H	och₃	ch₃	H	(B); 120°C
59	Bl	Br	OH	phenyl	H	(A); >260°C
60	Bl	Br	OH	phenyl	H	(B); 215°C
5	B2	Br	OCH₂CH₃	phenyl	H	(A); 162°C
6	B2	Br	och₂ch₃	phenyl	H	(B); 74°C
7	B3	Br	H	phenyl	H	(A); 98°C
8	B3	Br	H	phenyl	H	(B); 180°C
12	B7	Br	OCH₃	l-naphthyl	H	(Al); 118°C(foam);a=R,b=S; [alpha]_D ²⁰ = -166.98 (c=0.505g/100ml in DMF)
13	B7	Br	och₃	' l-naphthyl	H	(A2); 120°C (foam); a=S; b=R; [alpha]_D ²⁰ =+167.60 (c=0.472g/100ml in DMF)
12a	B7	Br	och₃	l-naphthyl	H	(Bl); [tx]_D ²⁰ =-42.56 (c = 0.336 g/100 ml in DMF)
13a	B7	Br	och₃	l-naphthyl	H	(B2); [a]_D ²⁰ =+43.55 (c = 0.349 g/100 ml in DMF)
14	B7	Br	och₃	l-naphthyl	H	(A); 210°C
15	B7	Br	och₃	l-naphthyl	H	(B); 244°C
45	B7	Br	och₃	2-naphthyl	H	(A); 262°C
46	B7	Br	och₃	2-naphthyl	H	(B); 162°C
67	B8	Br	och₃	2,5-difluorophenyl	H	(A); 60°C
68	B8	Br	och₃	2,5-difluorophenyl	H	(B); 208°C
110	B8	Br	och₃	2,5-difluorophenyl	H	(Al); 167°C
lll	B8	Br	och₃	2,5-difluorophenyl	H	(A2); oil
69	Bl	Br	OCH,	2-fluorophenyl	H	(A); oil
70	Bl	Br	OCH₃	2-fluorophenyl	JI_	(B); oil

Comp. m	. Εχ. nr.	R¹	R²	R³	r6	Stereochemistry and melting points
71	Β1	Br	och₃	l-naphthyl	ch₃	(A); 174°C
72	Β1	Br	och₃	l-naphthyl	ch₃	(B); 178°C
73	Β1	Br	och₃	l-naphthyl	Cl	(B); 174°C
74	Β1	Br	och₃	l-naphthyl	Cl	(A); 110°C
75	Β1	Br	och₃	CQ	H	(A); 196°C
76	Β1	Br	OCH₃	CO	H	(B); 130°C
77	Β1	Br	och₃	C0	H	(A); 202°C
78	Β1	Br	och₃	ω	H	(B); 202°C
79	Β1	Br	ΛΛ -N 0 UA	l-naphthyl	H	(A);>250°C
80	Β1	Br	OCH₃	4-cyanophenyl	H	(A); 224°C
81	Β1	Br	och₃	4-cyanophenyl	H	(B); 232°C
82	Β1	ch₃	OCH₃	l-naphthyl	H	(A); 202°C
83	Β1	ch₃	och₃	l-naphthyl	H	(B); 198°C
84	Β1	phenyl	och₃	l-naphthyl	H	(A); 248°C
85	Β1	phenyl	och₃	l-naphthyl	H	(B); 214°C
86	Β1	Br	och₃	Z=N	H	(A); 184°C
87	Β1	Br	och₃	z=N Ό	H	(B); 186°C
88	Β1	Br	sch₃	l-naphthyl	H	(A); 240°C
89	Β1	Br	och₃	~00	H	(A); 236°C
90	Β1	Br	OCHj	--Ov	H	(B); 206°C
91	Β1	H	och₃	l-naphthyl	H	(A); 178°C
92	Β1	H	och₃	l-naphthyl	H	(B); 160°C
93	Β1	H	och₃	3-fluorophenyl	H	(A); 178°C
94	Β1	H	och₃	3-fluorophenyl	H	(B); 182°C
95	Β1	Br	och₃	2-phenylethyl	H	(A); 178°C
96	Β1	Br	och₃	2-phenylethyl	H	(B); 146°C

Comp. n:	ri Ex. nr.	R¹	R²	R³	R⁶	Stereochemistry and melting points
97	B1	och₃	och₃	l-naphthyl	H	(A); 168°C
98	B1	och₃	och₃	l-naphthyl	H	(B); 154°C
113	B14	Br	och₃	2,3-difluorophenyl	H	(A); 128°C
114	B14	Br	och₃	2,3-difluorophenyl	H	(B); 213°C
115	B15	Br	och₃	3,5-difluorophenyl	H	(A); 192’C
116	B15	Br	och₃	3,5-difluorophenyl	H	(B); 224°C
117	B15	Br	och₃	3,5-difluorophenyl	H	(Al); 161°C
118	B15	Br	och₃	3,5-difluorophenyl	H	(A2); 158°C
119	B7	Cl	och₃	l-naphthyl	H	(A); 212°C
120	B7	Cl	och₃	l-naphthyl	H	(B); 236°C
122	B7	Br	och₃	1 1	H	(B); 227°C
127	B7	Br	och₃	5-bromo-2-naphthyl	H	(A); 226°C
130	B7	Br	och₃	5-bromo-2-naphthyl	H	(B); 220°C
131	B1	Br	och₃	6o	H	(A); 206°C
134	B9	och₃	och₃	3-fluorophenyl	H	(A); 172°C
135	B9	och₃	och₃	3-fluorophenyl	H	(B); 182°C
143	B7	Br	och₃	3 -bromo-1 -naphthyl	H	(A); 234°C
150	B7	Br	och₃	3 -bromo-1 -naphthyl	H	(B);212°C
159	B8	Br	och₃	2,5-difluorophenyl	H	(Al); 208°C
160	B8	Br	och₃	2,5-difluorophenyl	H	(A2); 167°C
162	B7	Br	och₃	6-methoxy-2-naphthyl	H	(A); 206°C
163	B7	Br	och₃	6-methoxy-2-naphthyl	H	(B); 206°C
164	B9	Br	?	3-fluorophenyl	H	(A); 118°C
165	B9	Br		3-fluorophenyl	H	(B); oil
167	B8	Br	och₃	2,6-difluorophenyl	H	(B); 180°C
174	B9	U-	och₃	3-fluorophenyl	H	(A); 159°C

Comp. ηι	i Ex. nr.	R¹	R²	R³	R⁶	Stereochemistry and melting points
175	B9	V-	och₃	3-fluorophenyl	H	(B); 196°C
176	B7	Br	to $	l-naphthyl	H	(A); oil
179	B9	CN	och₃	3-fluorophenyl	H	(A);213°C
180	B9	CN	och₃	3-fluorophenyI	H	(B); 163°C
181	B9	Br	och₃	4-fluorophenyl	H	(A); 198°C
182	B9	Br	OCHj	4-fluorophenyl	H	(B); 238°C
183	Bl	Br	och₃	3-trifluoro- methylphenyl	H	(A); 170°C
188	Bl	Br	och₃	l,4-pyrimidin-2-yl	H	(A); 110°C
189	Bl	Br	och₃	1,4-pyrimidin-2-yl	H	(B); 145°C
195	B15	Br	och₃	3,4-difluorophenyl	H	(A); 250°C
196	B15	Br	och₃	3,4-difluorophenyl	H	(B); 184°C
201	Bl	Br	och₃		H	(A); 214°C -
202	Bl	Br	och₃		H	(B); 246°C
203	B9		och₃	3-fluorophenyl	H	(A); 225°C
204	B9	0?..	OCHj	3-fluorophenyl	H	(B); 216°C
205	B7	Br	och₃	l-naphthyl	F	(A); 213°C
206	B7	Br	och₃	l-naphthyl	F	(B);213°C
207	B15	F	och₃	3,5-difluorophenyl	H	(A); 232°C
208	B15	F	och₃	3, 5-difluorophenyl	H	(B); 188°C
212	B7		OCHj	l-naphthyl	H	(B); 220°C

Comp. nr	Ex. nr.	R¹	R²	R³	R⁴	R⁵	Phys.data (salt/melting points) and stereo- chemistrv
18	B1	Br	och₃	phenyl	ch₂ch₃	ch₂ch₃	.ethanedioate (2:3); (A); 230°C
19	B1	Br	OCH₃	phenyl	ch₂ch₃	ch₂ch₃	.ethanedioate (2:3), (B); 150°C
44	B4	Br	OCH₃	phenyl	H	H	(A); 190°C
9	B4	Br	OCH₃	phenyl	H	H	(B); 204°C
141	B7	Br	och₃	2-naphthyl	ch₃	CH₂CH₃	(A); 188°C
142	B7	Br	och₃	2-naphthyl	ch₃	ch₂ch₃	(B); 202°C
230	B12	Br	och₃	l-naphthyl	ch₃	benzyl	/oil
147	B7	Br	och₃	l-naphthyl	ch₃	CH₂CH₃	(A); 168°C
148	B7	Br	och₃	l-naphthyl	ch₃	ch₂ch₃	(B); 212°C
56	B13	Br	och₃	l-naphthyl	ch₃	H	(A); 204°C
214	B13	Br	och₃	l-naphthyl	ch₃	H	(B); 225°C

-36Table3:

Comp.	Ex.	R³	L	Stereochemistiy
nr.	nr.			and melting points
47	B1	phenyl	l-piperidinyl	(A); 190°C
48	B1	phenyl	l-piperidinyl	(B);210°C
128	B1	2-naphthyl	l-piperidinyl	(A); 254°C
129	B1	2-naphthyl	l-piperidinyl	(B); 212°C
49	B1	phenyl	l-imidazolyl	(A);216°C
50	B1	phenyl	l-imidazolyl	(B); 230°C
51	B1	phenyl	1 -(4-methyl)piperazinyl	(A); 150°C
52	B1	phenyl	1 -(4-methyl)piperaziiiyl	(B); 230°C
53	B1	phenyl	l-(l,2,4-triazolyl)	(A); 180°C
54	B1	phenyl	l-(l,2,4-triazolyl)	(B); 142°C
55	B1	phenyl	thiomorpholinyl	(A); oil
57	B5	phenyl	⁺N^ \ r	(A); 244°C
10	B5	phenyl	\ r	(B); 198°C
58	B6	phenyl	K 0	(A); 208°C
11	B6	phenyl	⁺N^ \|\ 0	(B); 208°C

Comp. nr,	Ex. nr.	R³	L	Stereochemistry and melting points
99	Bil	l-naphthyl	K 0	(Al); 218°C
100	B6	l-naphthyl	\|\ o	(A2);218°C
101	B6	l-naphthyl	\|\ 0	(B); 175°C
102	B5	l-naphthyl	⁺N^ \ 1'	(A2); 210°C
103	B5	l-naphthyl	⁺N^ \ r	(B); >250°C
121	B5	1 -naphthyl	\ 1'	(Al); 210°C
123	B1	phenyl	morpholinyl	(A); 226°C
124	B1	phenyl	morpholinyl	(B); 210°C
136	B7	2-naphthyl	4-methylpyrazinyl	(A); 188°C
137	B7	2-naphthyl	4-methylpyrazinyl	(B); 232°C
139	B7	2-naphthyl	morpholinyl	(A); 258°C
140	B7	2-naphthyl	morpholinyl	(B); 214°C
144	B7	2-naphthyl	pyirolidinyl	(A); 238°C
145	B7	1 -naphthyl	l-piperidinyl	(A); 212°C
146	B7	l-naphthyl	l-piperidinyl	(B); 220°C
149	B7	l-naphthyl	4-methylpyrazinyl	(B); 232°C
151	B7	3 -bromo-1 -naphthyl	4-methylpiperazinyl	(A); 178°C
152	B7	3 -bromo-1 -naphthyl	4-methylpiperazinyl	(B); 226°C
153	B7	6-bromo-2-naphthyl	4-methylpiperazinyl	(A); 208°C
154	B7.......ļ	6-bromo-2-naphthyl	4-methylpiperazinyl	(B); 254°C

Comp. nr.	Ex. ņr.	R³	L	Stereoehenustry andmelting 'points
155	B7	6-bromo-2-naphthyl	l-piperidinyl	(A); 224°C
156	B7	l-naphthyl	4-methylpiperazinyl	(A); 200°C
157	B7	6-bromo-2-naphthyl	l-pyrrolidinyl	(B); 220°C
158	B7	l-naphthyl	morpholinyl	(B); 272°C
166	B7	6-bromo-2 -naphthyl	l-piperidinyl	(B);218°C
170	B7	2-naphthyl	l-pyrrolidinyl	(A); 238°C
171	B7	2-naphthyl	l-pyrrolidinyl	(B);218°C
172	B7	l-naphthyl	l,2,4-triazol-l-yl	/142°C
173	B7	l-naphthyl	l,2-imidazol-l-yl	(A); 222°C
177	B7	6-bromo-2-naphthyl	morpholinyl	(A); 242°C
178	B7	6-bromo-2 -naphthyl	morpholinyl	(B); 246°C
187	B7	l-naphthyl	l,2-imidazol-l-yl	(B); 236°C
200	B7	2-naphthyl		(A); 254°C
209	B7	2-naphthyl	-N N-% ) ' ' N—^J	(B); 198°C

Table 4:

Comp. nr.	Ex. nr.	R³	Q	L	Stereochemistrv andmelting points
61	B1	phenyl	0	N(CH₃)₂	(A); 220°C
62	B1	phenyl	0	N(CH₃)₂	(B); 194°C
63	B1	phenyl	2	N(CH₃)₂	(A); 150°C
64	B1	phenyl	2	N(CH₃)₂	(B); 220°C
125	B7	2-naphthyl	2	N(CH₃)₂	(A); 229°C
126	B7	2-naphthyl	2	N(CH₃)₂	(B); 214°C

Comp. nr.	Εχ. nr.	R³	Q	L	Stereochemistry and melting points
65	B1	phenyl	3	N(CH₃)₂	(A); 130°C
66	B1	phenyl	3	N(CH₃)₂	(B); 170°C
132	B7	2-naphthyl	2	pyrrolidinyl	(A); 227°C
133	B7	2-naphthyl	2	pyrrolidinyl	(B); 222°C
161	B7	2-naphthyl	2	morpholinyl	(B); 234°C
186	B7	l-naphthyl	2	N(CH₃)₂	(A); 187°C
190	B7	2-naphthyl	3	N(CH₃)₂	(A); 170°C
191	B7	2-naphthyl	3	N(CH₃)₂	(B); 145°C
192	B7	2-naphthyl	2	N(CH₂CH₃)₂	(A); 90°C
193	B7	2-naphthyl	2	N(CH₂CH₃)₂	(B); 202°C
194	B7	l-naphthyl	2	pyrrolidinyl	(B); 206°C
197	B7	l-naphthyl	3	N(CH₃)₂	(A); 160°C
198	B7	2-naphthyl	2	morpholinyl	(A);215°C
199	B7	l-naphthyl	2	N(CH₂CH₃)₂	(A); 185°C
210	B7	l-naphthyl	2	moipholinyl	(B); 222°C
211	B7	l-naphthyl·	2	morpholinyl	(A); 184°C

Comp. nr.	Ex. nr.	R³	RS	R⁹	Stereochemistry and melting points
104	B1	phenyl	-CH=	=CH-N=	(A); 170°C
105	B1	phenyl	-CH=	=CH-N=	(B); 150°C
106	B1	phenyl	CH₃	=0	(A); 224°C
107	B1	phenyl	ch₃	=0	(B); 180°C
138	B7	l-naphthyl	H	=0	(Al);>260°C

-40Table 6:

3omp. nr.	Ex. nr.	r^!	R³	R⁶	Sterechemistry and melting points
		a	b	c	d
215	B9	H	Br	CH₃	H	3-fluorophenyl	H	(A); 197°C
216	B9	H	Br	ch₃	H	3-fluorophenyl	H	(B); 158°C
217	B7	H	H	Br	H	l-naphthyl	H	(A); 212°C
218	B7	H	H	Br	H	l-naphthyl	H	(B); 172°C
219	B9	H	Br	H	ch₃	3-fluorophenyl	H	(A); 220°C
220	B9	H	Br	H	ch₃	3-fluorophenyl	H	(B); 179°C
221	B7	Br	H	H	H	l-naphthyl	H	(A); 170°C
224	B7	Br	H	H	H	l-naphthyl	H	/205°C
222	B7	H	Br	H	H	l-naphthyl	3 '4	(A); 155°C
223	B7	H	Br	H	H	l-naphthyl		(B); 205°C
225	B7	H	Br	ch₃	H	l-naphthyl	H	(A); 238°C
226	B7	H	Br	ch₃	H	l-naphthyl	H	(B); 208°C
227	B15	H	Br	ch₃	H	3,5 -difluorophenyl	H	(A); 195°C
228	B15	H	Br	ch₃	H	3, 5-difluorophenyl	H	(B); 218°C
229	B7	H	ch₃	ch₃	H	l-naphthyl	H	(A); 238°C

-41PHARMACOLOGICAL PART

A. Studv of the effect of final compound 12 in killing dormant Mvcobacterium bovis

Bacterial strains and Culture medium

Mycobacterium bovis BCG vvere obtained from Tibotec Virco (TB0087- (Belgium).

M. bovis BCG, expressing the luciferase gene on plasmid pSMTl (a kind gift from Dr. Kriš Huygen at Pasteur Institute, Brussles⁸) vvere cultured in Middlebrook 7H9 medium (Difco, BD271310) vvith 0.05% Tvveen-80 (Sigma) in log phase for a period of 3-4 days before start of the experiment.

To prepare grovvth medium vvith supplements: dissolve 4.7 g of the Middlebrook povvder in 895 ml distilled vvater and add 5 ml Glycerol, 200 μΐ Tvveen 80 and autoclave at 121°C for 15 minūtes. Aseptically add 100 ml Middlebrook OADC enrichment to the medium vvhen cooled to 45 °C. Store at 4°C for maximum 1 month. Pre-incubate ali media 2 days at 37°C to check for contamination. Add 50 pg/ml hygromycin for strain M. bovis BCG expressing the luciferase gene (BCG-pSMTl).

I. Study vvith Mycobacterium bovis BCG Dormancy assay

500 pl of Mycobacterium bovis BCG stock vvas added to 100 ml Middlebrook 7H9 broth vvith supplements in a 250 ml sterile Duran bottle vvith a magnetic stirring rod. Incubation vvas done on an electric magnetic stirrer for 7 days at 37 °C (500 rpm). 5 ml aliquots of log phase culture (ODeoonm =0-5 to 0.8) vvere transferred into 15 ml serevv capped falcon tubes. Various drugs vvere added to the individual tubes to a final concentration of 10 pg/ml. After the addition of the drugs, ali tube vvere closed loosely and placed inside an anaerobic jar (BBL). Anaerobic gas generation envelopes vvere used to get anaerobic conditions in the jar and anaerobic strips to monitor the anaerobic conditions. The addition of the individual drugs and the start of the anaerobiosis vvithin the jar vvas done extremely quickly as previously described⁹. The jar vvas incubated for 7 days at 37 °C.

CFU assay

After 7 days of anaerobiosis, the dormant cultures vvere collected by lovv speed centrifugation (2000 rpm for 10 minūtes). The celis vvere vvashed tvvice vvith 7H9 medium so as to remove the drugs and resuspended in drug free medium. The CFU of the treated and untreated cultures vvere determined by plating at day 0, 2, and day 5 to evaluate the bactericidal activity.

-42II. Study vvith M. bovis BCG, expressing the luciferase gene on plasmid pSMTl Dormancy assay

500 μΐ of Mycobacterium bovis BCG luciferase (pSMTl) stock was added to 100 ml Middlebrook 7H9 broth vvith supplements in a 250 ml sterile Duran bottle vvith a magnetic stirring rod. Incubation vvas done on an electric magnetic stirrer for 7 days at 37 °C (500 rpm). 5 ml aliquots of log phase culture (ODgoonm =0-5 to 0.8) vvere transferred into 15 ml screvv capped falcon tubes. Various drugs vvere added to the individual tubes to a final concentration of 10 pg/ml. After addition of the drugs, ali tube vvere closed loosely and placed very quickly inside an anaerobic jar (BBL) as previously described⁹. Anaerobic gas generation envelopes vvere used to get anaerobic conditions in the jar and anaerobic strips to monitor the anaerobic conditions. The jar vvas incubated for 7 days at 37 °C.

Luciferase assay

After 7 days of anaerobiosis, the dormant cultures vvere collected by lovv speed centrifugation (2000 rpm for 10 minūtes). The celis vvere vvashed tvvice vvith 7H9 medium so as to remove the drugs and resuspended in drug free medium. After vvashing, 250 μΐ of the dormant M. bovis BCG luciferase (pSMTl) vvas added to 5 different microplates (day 0 to day 5). Every sample vvas diluted in microplates (5-fold dilutions) in medium and incubated again for 37 °C from 0 to 5 days. 40 μΐ of samples and dilutions vvere added to 140 μΐ PBS. 20 μΐ luciferase substrate (1% n-decyl aldehyde in ethanol) vvas added. The luminescence vvas measured for 10 seconds to follovv the grovvth of the viable bacteria on every day from 0 to 5 days (Use Luminoskan Ascent Labsystems vvith injector).

Experimental organization:__

Sample number	Strain M.Bovis	Sample/compound	microgram/ml
1-2	BCG	Control
3	BCG	Metronidazole	10
4	BCG	Isoniazid	10
5-6	BCG	Final compound 12	10
7-8	BCG	Final compound 12	1
9-10	BCG	Final compound 12	0.1
11-12	BCG/pSMTl	Control
13	BCG/pSMTl	Metronidazole	10
14	BCG/pSMTl	Isoniazid	10
15-16	BCG/pSMTl	Final compound 12	10

Sample number	Strain M.Bovis	Sample/compound	microgram/ml
17-18	BCG/pSMTl	Final compound 12	1
19-20	BCG/pSMTl	Final compound 12	0.1

Results and Discussion

An in vitro dormancy modei of dormancy was developed based on Wayne’s method of creating dormant bacteria by oxygen depletion ^9,I°. In Wayne’s modei as mycobacteria settle dovvn to the bottom of the flask they generate an oxygen gradient creating anaerobic conditions at the bottom of the flask. This transition to lovv oxygen concentrations causes mycobacteria to become dormant and that leads to upregulated expression of several genes including isocitrate lyase and glycine dehydrogenase⁷. These enzymes are responsible for production of energy in absence of oxygen and the termiņai electron acceptors are nitrate, sulfates etc as compared to molecular oxygen in case of aerobie respiration. The energy of reduced substrates generates a electron Chemical gradient.

In this experiment, an adaptation of Wayne’s modei vvas used in the experimental set up involving the use of gaspak anaerobic jars in vvhich oxygen is depleted in the chamber by means of a Chemical reaction⁹. Gaspak jars are fitted vvith a lid containing a catalyst. A Gaspak foil envelope containing substances that generate hydrogen and CO2 is placed in the jar vvith the bacterial GUltures. The envelope is opened, and 10 ml of tap vvater is pipetted into it. When the jar is closed (the lid is clamped dovvn tightly), the hydrogen given off combines vvith oxygen, through the mediation of the catalyst, to form vvater. This leads to the gradual depletion of the oxygen present in the chamber and as such creates the oxygen gradient. Furthermore, an indicator strip in the jar contains methylene blue, vvhich tums colourless in the absence of oxygen. The colour . change in the indicator strip signifies that the proper atmospheric condition has been achieved.

For rapid analysis of the effect of the cornpound on the dormant bacteria, M. bovis

BCG transformed vvith the luciferase construct vvas used. M. bovis BCG has been used in earlier experiments as a surrogate to mimic dormancy in mycobacteria in general and M. tuberculosis in particular^11,12. Luciferase reporter strains have been used quite often to access the viability of the bacteria ^13,14. The M. bovis BCG is transformed vvith the reporter plasmid pSMTl, vvhich is a shuttle vector containing the origin of replication of E.coli and mycobacteria⁸. The luminescent genes from Vibro harveyi (lux A and B) are under control of BCG hsp60 promoter and producē light in presence of ATP or Flavin mononueleotide (FMNH₂). Dead celis are not able to producē these cofactors, thus corresponding to decline in luminescence.

-44The activity of final compound 12 in this dormancy assay vvas analysed as vvell as the activity of other drugs including metronidazole and Isoniazid. Dormant bacteria are not killed by Isoniazid and to some extent are also resistant to rifampicin but are susceptible to killing by metronidazole, an antibiotic for anaerobic pathogens ^15,16.

Isoniazid acts as an early bactericidal aģent and its activity is limited to killing of replicating bacilli but does not have a significant sterilizing activity on dormant bacilli 17

After 7 days of anaerobiosis, the bacteria vvere suspended in drug free medium for 5 days and the effect of different compounds on bacterial viability vvas assayed by Luciferase counts. As shovvn in Figurē 1, Isoniazid had no effect on these dormant bacteria and these bacteria had almost similar grovvth characteristics as compared to control, demonstrating the dormant or non-replicating status ofthe cultured bacilli. In contrast, metronidazole vvas clearly effective in killing the dormant bacilli over a period of time vvith reduction of 2 logio as compared to control. Final compound 12 affects the survival of the dormant bacteria in concentration dependent manner. At 10 pg/ml concentration of final compound 12 there vvas approximately 4-logio reduction in bacterial survival as compared to untreated control. At 0.1 and 1 pg/ml of the compound the corresponding killing of dormant bacteria vvas about 0.5 logio and 2 logio respectively.

To correlate the effects of final compound 12 on bacteria killing in terms relative luminescence units (RLU/ml) versus colony forming units (CFU/ ml), bacterial counts vvere also measured on 7H10 plates. A similar ratio of RLU units vvith the CFU counts vvas observed after plating the day 2 and day 4 samples on 7H10 plates. The reduction in CFU counts compared vvith that of untreated control shovved that final compound 12 at 10 pg/ml, 1 pg/ml and 0.1 pg/ml reduced the viability by approximately 4, 2.3, and 0.5 logio at day 2 and about 6, 4.7 and 1.1 logio at day 5 respectively. Fig 2 (A and B) reports CFU data. A close coirelation vvas observed betvveen luminescence and the CFU during various stages of the experiment. Interestingly there vvas marked reduction in RLUs at time point 0 as compared to CFU counts, primarily because ATP concentration vvithin these celis is very lovv, vvhich has been shovvn to be the characteristics of the metabolic State of the dormant bacilli⁸.

The activity of final compound 12 on dormant (non-multiplying) mycobacteria is an extremely important finding, as it vvill help in the fight against tuberculosis by eradicating the disease in individuāls vvho are at risk of developing TB.

-45B. Studv of the effect of present compounds in killing dormant Mvcobacterium tuberculosis according to the Wayne dormancv modei*

Bacterial strain and Culture medium

Mycobacterium tuberculosis (H37RV) vvas cultured in Middlebrook medium vvith 5 0.05% Tvveen.

To prepare Middlebrook 7H9 Broth (IX) (BD 271310) vvith supplements rdissolve 4.7 g of the Middlebrook povvder in 895 ml distilled vvater and add 5 ml Glycerol, 200 μΐ Tvveen 80 and autoclave at 121 °C for 15 minūtes. Aseptically add 100 ml Middlebrook OADC Enrichment (BD 211886) to the medium vvhen cooled to 45 °C.

Store at 4 °C for maximum 1 month. Pre-incubate all media 2 days at 37 °C to check for contamination.

* Wayne L.G. et al.; Infection and Immunity 64 (6), 2062-2069 (1996)

Study vvith Mycobacterium tuberculosis (H37RV)

Dormancy assay

1000 μΐ of Mycobacterium tuberculosis stock (previous culture) vvas added to 100 ml Middlebrook 7H9 broth vvith supplements in a 250 ml sterile Duran bottle vvith a magnetic stirring rod. Incubation vvas done on an electric magnetic stirrer for 7 days at

37 °C (500 rpm). 17 ml aliquots of log phase culture (calculated Οϋήοοητη = 0.01) vvere transferred into 25 ml tubes. The tubes vvere tightly closed vvith caps vvith rubber septa and incubated on a magnetic stirring plate to create anaerobiosis by oxygen depletion. Stirring in the tubes vvas achieved vvith 8 mm teflon stirring bar. The tubes vvere incubated for 22 days at 37 °C in an incubator on a magnetic stirring plate (120 rpm) until anaerobiosis (methylene blue (1.5 mg/liter) is tumed to colourless). After 14 days various drugs (final concentration of 100,10,1 and 0.1 pg/ml) vvere added to the individual tubes. Metronidazole vvas added as control to kill the dormant bacteria (added at start). Isoniazid vvas added as control to shovv that it does not have any effect on grovvth and viability of dormant bacteria.

CFU assay

After 22 days, the cultures vvere collected by lovv speed centrifugation (2000 rpm for 10 minūtes). The celis vvere vvashed tvvice vvith drug free medium and the celis vvere resuspended in drug-free medium and incubated. The reduction in CFU compared to untreated control cultures, vvas determined by plating after anaerobiosis to evaluate the bactericidal activity.

-46Experimental organization

Sample number	Sample / Compound	pg/ml
1-2	Control	-
3-4	Metronidazole	100
5-6	Isoniazid	10
7 - 8	Moxifloxacin	10
9- 10		1
11 - 12	Final compound 12	10
13 - 14		1
15-16	Rifampicin	10
17-18		1

Results and Discussion:

The effect of the final compound 12 on dormant bacteria is demonstrated (see Fig. 3) using the Wayne dormancy modei. As already indicated above, it is an in vitro oxygen depletion modei, vvhich triggers a dormancy response in the bacteria¹⁸'²³. In Wayne modei, cultures of the bacterium are subjected to the gradual oxygen depletion by incubation in stirred sealed tubes. With slovv shift of the aerobie grovving bacteria to anaerobic conditions, the culture is more capable to adapt and survive the anaerobiosis by shifting dovvn to a state of anaerobic persistence. Wayne modei is a vvelicharacterized in vitro modei for dormancy.

At 10pg/ml concentration of final compound 12, more than 2 logio reduction of the dormant bacteria vvas observed as also seen in case of moxifloxacin and rifampin. At lpg/ml concentration, 1.41 logio reduction vvas observed for compound 12.

Compounds 71, 75, 172 and 125 vvere also tested in the same tēst. At 10pg/ml concentration, more than 2 logi o reduction of the dormant bacteria vvas observed for compound 71; 1.14 logio reduction vvas observed for compound 75; 0.98 logio reduction vvas observed for compound 172; 0.23 logio reduction vvas observed for compound 125. At lņg/ml concentration, 1.55 logio reduction vvas observed for compound 71; 0.87 logio reduction vvas observed for compound 75; 0,29 logio reduction vvas observed for compound 172.

Isoniazid did not have any effect on dormant bacteria vvhile the control compound, metronidazole shovved good efficacy.

Claims

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7. Gomez,J.E. & McKinney,J.D. M. tuberculosis persistence, latency, and drug tolerance. Tuberculosis. (Edinb.) 84, 29-44 (2004).

25 8. Snewin,V.A. et al. Assessment of immunity to mycobacterial infection vvith luciferase reporter constructs. Infect. Immun. 67, 4586-4593 (1999).

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10. Wayne,L.G. Synchronized replication of Mycobacterium tuberculosis. Infect.

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-4811. Boon,C. & Dick,T. Mycobacterium bovis BCG response regulator essential for hypoxic dormancy. JBacteriol. 184, 6760-6767 (2002).

12. Hutter,B. & Dick,T. Up-regulation of narX, encoding a putative 'fused nitrate reductase' in anaerobic dormant Mycobacterium bovis BCG. FEMS Microbiol. Leti.

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14. Hickey,M.J. et al. Luciferase in vivo expression technology: use of recombinant mycobacterial reporter strains to evaiuate antimycobacterial activity in mice.

10 Antimicrob. Aģents Chemother. 40, 400-407 (1996).

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16. Wayne,L.G. Dormancy of Mycobacterium tuberculosis and latency of disease. Eur. J Clin Microbiol. Infect. Dis 13, 908-914 (1994).

15 17. Lalande,V., Truffot-Pemot,C., Paccaly-Moulin,A., Grosset,J. & Ji,B. Povverful bactericidal activity of sparfloxacin (AT-4140) against Mycobacterium tuberculosis in mice. Antimicrob. Aģents Chemother. 37, 407-413 (1993).

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25 Chemother. 45, 2403-2404 (2001).

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Mycobacterium smegmatis. FEMS Microbiol. Lett. 167, 7-11 (1998).

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Mycobacterium tuberculosis through two stages of nonreplicating persistence. Infect. Immun. 64, 2062-2069 (1996).

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5 mycobacterial infections. Proc. Biol. Sci. 263, 257-263 (1996).

-50Claims

1. Use of a compound of formula (la) or (Ib) for the manufacture of a medicament for the treatment of latent tuberculosis, wherein the compound of formula (la) or (Ib) is a pharmaceutically acceptable acid or base addition salt thereof, a quatemary amine thereof, a 7V-oxide thereof, a tautomeric form thereof or a stereochemically isomeric form thereof wherein

R¹ is hydrogen, halo, haloalkyl, cyano, hydroxy, Ar, Het, alkyl, alkyloxy, alkylthio, alkyloxyalkyl, alkylthioalkyl, Ar-alkyl or di(Ar)alkyl;

p is an integer equal to 1, 2, 3 or 4 ;

R is hydrogen, hydroxy, mercapto, alkyloxy, alkyloxyalkyloxy, alkylthio,

R³ q

R⁴ and R⁵ mono or di(alkyl)amino or a radical of formula

CH₂, 0, S,NHorN-alkyl;

is alkyl, Ar, Ar-alkyl, Het or Het-alkyl;

is an integer equal to zero, 1, 2, 3 or 4 ;

each independently are hydrogen, alkyl or benzyl; or wherein Y is

-51R⁴ and R⁵ together and including the N to vvhich they are attached may form a radical selected from the group of pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, 2-imidazolinyl,.2-pyrazolinyl, imidazolyl, pyrazolyl, tnazolyl, piperidinyl, pyridinyl, piperazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, morpholinyl and thiomorpholinyl, each of said ring systems optionally substituted vvith alkyl, halo, haloalkyl, hydroxy, alkyloxy, amino, mono- or dialkylamino, alkylthio, alkyloxyalkyl, alkylthioalkyl and pyrimidinyl;

R⁶ is hydrogen, halo, haloalkyl, hydroxy, Ar, alkyl, alkyloxy, alkylthio, alkyloxyalkyl, alkylthioalkyl, Ar-alkyl or di(Ar)alkyl; or tvvo viciņai R⁶ radicals may be taken together to form a bivalent radical of formula -CH=CH-CH=CH-;

r is an integer equal to 1,2, 3, 4 or 5 ;

R⁷ is hydrogen, alkyl, Ar or Het;

g

R is hydrogen or alkyl;

R⁹ is oxo ; or

R⁸ and R⁹ together form the radical =N-CH=CH-;

alkyl is a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms ; or is a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms ; or is a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms attached to a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms ; vvherein each carbon atom can be optionally substituted vvith halo, hydroxy, alkyloxy or oxo ;

Ar is a homocycle selected from the group of phenyl, naphthyl, acenaphthyl, tetrahydronaphthyl, each homocycle optionally substituted vvith 1, 2 or 3 substituents, each substituent independently selected from the group of hydroxy, halo, cyano, nitro, amino, mono- or dialkylamino, alkyl, haloalkyl, alkyloxy, haloalkyloxy, carboxyl, alkyloxycarbonyl, aminocarbonyl, morpholinyl and mono- or dialkylaminocarbonyl;

Het is a monocyclic heterocycle selected from the group of 7v-phenoxypiperidmyl, piperidīnyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; or a bicyclic heterocycle selected from the group of quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2,3dihydrobenzo[l,4]dioxinyl or benzo[l,3]dioxolyl; each monocyclic and

-52bicyclic heterocycle may optionally be substituted vvith 1, 2 or 3 substituents selected from the group of halo, hydroxy, alkyl, alkyloxy or Ar-carbonyl;

halo is a substituent selected from the group of fluoro, chloro, bromo and iodo; and haloalkyl is a straight or branched saturated hydrocarbon radical having from 1 to

5 6 carbon atoms or a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms, vvherein one or more carbon atoms are substituted vvith one or more halo-atoms.
2. Use according to claim 1 vvherein

R¹ is hydrogen, halo, cyano, Ar, Het, alkyl, and alkyloxy ;

p is an integer equal to 1 or 2;

R² is hydrogen, hydroxy, alkyloxy, alkyloxyalkyloxy, alkylthio or a radical of formula vvherein Y is 0;

R³ is alkyl, Ar, Ar-alkyl or Het;

q is an integer equal to zero, 1, 2, or 3 ;

R⁴ and R⁵ each independently are hydrogen, alkyl or benzyl; or

R⁴ and R³ together and including the N to vvhich they are attached may form a radical selected from the group of pyrrolidinyl, imidazolyl, triazolyl, piperidinyl, piperazinyl, pyrazinyl, morpholinyl and thiomorpholinyl, each ring system optionally substituted vvith alkyl or pyrimidinyl;

R⁶ is hydrogen, halo or alkyl; or tvvo viciņai R⁶ radicals may be taken together to form a bivalent radical of formula

-CH=CH-CH=CH-; r is an integer equal to 1 ;

R⁷ is hydrogen;

o

R is hydrogen or alkyl;

R⁹ is oxo ; or

R⁸ and R⁹ together form the radical =N-CH=CH-;

alkyl is a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms; or is a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms ; or is a a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms attached to a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms; vvherein each carbon atom can be optionally substituted vvith halo or hydroxy ;

-53Ar is a homocycle selected from the group of phenyl, naphthyl, acenaphthyl, tetrahydronaphthyl, each homocycle optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from the group of halo, haloalkyl, cyano, alkyloxy and morpholinyl;

Het is a monocyclic heterocycle selected from the group of A-phenoxypiperidinyl, piperidinyl, iuranyl, thienyl, pyridinyl, pyrimidinyl; or a bicyclic heterocycle selected from the group of benzothienyl, 2,3-dihydrobenzo[l,4]dioxinyl or benzo[l,3]dioxolyl; each monocyclic and bicyclic heterocycle may optionally be substituted with 1, 2 or 3 alkyl or Ar-carbonyl substituents ; and halo is a substituent selected from the group of fiuoro, chioro and bromo.
3. Use according to claim 1 or 2 wherein in formula (la) or (Ib) R¹ is hydrogen, halo,

Ar, alky 1 or alkyloxy.
4. Use according to claim 3 wherein R¹ is halo.
5. Use according to any one of the preceding claims wherein in formula (la) or (Ib) p is equal to 1.
6. Use according to any one of the preceding claims vvherein in formula (la) or (Ib) R²is hydrogen, alkyloxy or alkylthio.
7. Use according to claim 6 wherein R² is alkyloxy.
8. Use according to any one of the preceding claims vvherein in formula (la) or (Ib) R³ is naphthyl, phenyl or thienyl, each optionally substituted vvith 1 or 2 substituents selected from the group of halo and haloalkyl.
9. Use according to claim 8 vvherein R³ is naphthyl.
10. Use according to any one of the preceding claims vvherein in formula (la) or (Ib) q is equal to 1.
11. Use according to any one of the preceding claims vvherein in formula (la) or (Ib) R⁴and R⁵ each independently are hydrogen or alkyl or R⁴ and R⁵ together and including the N to vvhich they are attached form a radical selected from the group of imidazolyl, triazolyl, piperidinyl, piperazinyl and thiomorpholinyl.

-5412. Use according to claim 11 vvherein in formula (la) or (Ib) R⁴ and R⁵ each independently are hydrogen or alkyl.

5 13. Use according to claim 12 vvherein R⁴ and R⁵ are Ci_4alkyl.
14. Use according to any one of the preceding claims vvherein in formula (la) or (Ib) R⁶is hydrogen, alkyl or halo.

10 15. Use according to claim 14 vvherein R⁶ is hydrogen.

16. Use according to any one of the preceding claims vvherein in formula (la) or (Ib) r is equal to 1.
15 17. Use according to any one of the preceding claims vvherein in formula (la) or (Ib) R⁷ is hydrogen.
18. Use according to claim 1 vvherein in formula (la) or (Ib) R¹ is hydrogen, halo, Ar, alkyl or alkyloxy; p = 1; R² is hydrogen, alkyloxy or alkylthio; R³ is naphthyl,

20 phenyl or thienyl, each optionally substituted vvith 1 or 2 substituents selected from the group of halo and haloalkyl; q = 0, 1, 2 or 3; R⁴ and R⁵ each independently are hydrogen or alkyl or R⁴ and R⁵ together and including the N to vvhich they are attached form a radical selected from the group of imidazolyl, triazolyl, piperidinyl, piperazinyl and thiomorpholinyl; R⁶ is hydrogen, alkyl or halo; r is

25 equal to 1 and R⁷ is hydrogen.
19. Use according to any one of the preceding claims vvherein alkyl represents Cj.

₆alkyl.

30 20. Use according to any one of the preceding claims vvherein haloalkyl represents polyhaloCi_6alkyl.

21. Use according to claim 1, characterized in that the compound is selected from the group consisting of:

35 ο 1 -(6-bromo-2-methoxy-quinolin-3-yl)-2-(3,5-difluoro-phenyl)-4dimethylamino-l -phenyl-butan-2-ol;

-55ο 1 -(6-bromo-2-methoxy-quinolin-3-yl)-4-dimethylamino-2-naphthalen-1 -yl-1 phenyl-butan-2-ol;

o l-(6-bromo-2-methoxy-quinolin-3-yl)-2-(2,5-difluoro-phenyl)-4dimethylamino-l -phenyl-butan-2-ol;

5 o l-(6-bromo-2-methoxy-quinolin-3-yl)-2-(2,3-difluoro-phenyl)-4dimethylamino-1 -phenyl-butan-2-ol;

ο 1 -(6-bromo-2-methoxy-quinolin-3-yl)-4-dimethylamiūo-2-(2-fluoro-phenyl)-1 phenyl-butan-2-ol;

ο 1 -(6-bromo-2-methoxy-quinolin-3-yl)-4-dimethylamino-2-naphthalen-1 -yl-1 -p10 tolyl-butan-2-ol;

ο 1 -(6-bromo-2-methoxy-quinoIin-3-yl)-4-methylamino-2-naphthalen-l -yl-1 phenyl-butan-2-ol;

o l-(6-bromo-2-methoxy-quinoiin-3-yl)-4-dimethyiamino-2-(3-fluoro-phenyl)-iphenyl-butan-2-ol; and

15 ο 1 -(6-bromo-2-methoxy-quino lin-3-yl)-4-dimethylamino-2-phenyl-1 -phenylbutan-2-ol;

a pharmaceutically acceptable acid or base addition salt thereof, a 2V-oxide thereof, a tautomeric form thereof or a stereochemically isomeric form thereof.
20 22. Use according to claim 1 vvherein the compound is selected from the group consisting of o l-(6-bromo-2-methoxy-quinolin-3-yl)-2-(2,3-difluoro-phenyl)-4-dimethylamino-lphenyl-butan-2-ol;

ο 1 -(6-bromo-2-methoxy-quinolin-3-yl)-4-dimethylamino-2-naphthalen-1 -yl-1 25 phenyl-butan-2-ol;

a pharmaceutically acceptable acid or base addition salt thereof, a V-oxide thereof, a tautomeric form thereof or a stereochemically isomeric form thereof.
23. Use according to claim 1 vvherein the compound is

-56a pharmaceutically acceptable acid or base addition salt thereof, a 7v-oxide thereof, or a stereochemically isomeric form thereof.
24. Use according to claim 23 vvherein the compound is or a pharmaceutically acceptable acid addition salt thereof.
25. Use according to claim 23 vvherein the compound is

Br

10 or a stereochemically isomeric form thereof.
26. Use according to claim 23 vvherein the compound is

Br or a yV-oxide form thereof.
27. Use according to claim 23 vvherein the compound is or a pharmaceutically acceptable acid addition salt thereof.
28. Use according to claim 27 vvherein the compound is

-1/3FIG. 1 kontrole metronidazols (10 pg/ml) >

_i

0C

E ra o

1 0 1 2 3 4 5

Dienas pec anaerobiozes izoniazīds (10 pg/ml) gala savienojums 12 (10 pg/ml) x gala savienojums 12 (1 pg/ml) _t gala savienojums 12 (0,1 μg/ml)

Drug: Anaerobic - Medikaments: Anaerobisks No drug: Aerobie - Bez medikamenta: Aerobisks