USE OF COMPOUNDS FOR THE PREVENTION AND/OR TREATMENT OF ANKYLOSING SPONDYLITIS, AND CORRESPONDING COMPOSITIONS

Abstract

The invention concerns a compound of formula (I) and/or a compound of formula (Ia) for use in the prevention and/or treatment of ankylosing spondylitis, as well as compositions and combination preparations comprising them.

Claims

1. Compound of the formula (I): ##STR00062## or a pharmaceutically acceptable stereoisomer, salt, hydrate, solvate, or crystal thereof, wherein X is selected from O, CH.sub.2, S, Se, CHF, CF.sub.2, C═CH.sub.2; R.sub.1 is selected from H, azido, cyano, C.sub.1-C8 alkyl, C.sub.1-C8 thioalkyl, C.sub.1-C8 heteroalkyl, and OR; wherein R is selected from H and C.sub.1-C8 alkyl; R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are selected independently of one another from H, halogen, azido, cyano, hydroxyl, C.sub.1-C12 alkyl, C.sub.1-C12 thioalkyl, C.sub.1-C12 heteroalkyl, C.sub.1-C12 haloalkyl, and OR; wherein R is selected from H, C.sub.1-C.sub.12 alkyl, C(O)(C.sub.1-C.sub.12) alkyl, C(O)NH(C.sub.1-C.sub.12) alkyl, C(O)O(C.sub.1-C.sub.12) alkyl, C(O) aryl, C(O)(C.sub.1-C.sub.12) alkylaryl, C(O)NH(C.sub.1-C.sub.12) alkylaryl, C(O)O(C.sub.1-C.sub.12) alkylaryl, and C(O)CHR.sub.AANH.sub.2; wherein R.sub.AA is a side chain selected from the proteinogenic amino acids; R.sub.6 is selected from H, azido, cyano, C.sub.1-C8 alkyl, C.sub.1-C8 thioalkyl, C.sub.1-C8 heteroalkyl, and OR; wherein R is selected from H and C.sub.1-C8 alkyl; R.sub.7 is selected from H, P(O)R.sub.9R.sub.10, and P(S)R.sub.9R.sub.10; wherein R.sub.9 and R.sub.10 are selected independently of one another from OH, OR.sub.11, NHR.sub.13, NR.sub.13R.sub.14, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C10 cycloalkyl, C.sub.5-C12 aryl, (C.sub.1-C.sub.8) alkylaryl, (C.sub.1-C.sub.8) arylalkyl, (C.sub.1-C.sub.8) heteroalkyl, (C.sub.1-C.sub.8) heterocycloalkyl, heteroaryl, and NHCHR.sub.AR.sub.A′C(O)R.sub.12; wherein: R.sub.11 is selected from a C.sub.1-C10 alkyl, C.sub.3-C10 cycloalkyl, C.sub.5-C18 aryl, C.sub.1-C10 alkylaryl, substituted C.sub.5-C12 aryl, C.sub.1-C10 heteroalkyl, C.sub.3-C10 heterocycloalkyl, C.sub.1-C.sub.10 haloalkyl, heteroaryl, —(CH.sub.2).sub.nC(O)(C.sub.1-C.sub.15) alkyl, —(CH.sub.2).sub.nOC(O)(C.sub.1-C.sub.15) alkyl, —(CH.sub.2).sub.nOC(O)O(C.sub.1-C.sub.15) alkyl, —(CH.sub.2).sub.nSC(O)(C.sub.1-C.sub.15) alkyl, —(CH.sub.2).sub.nC(O)O(C.sub.1-C.sub.15) alkyl, and —(CH.sub.2).sub.nC(O)O(C.sub.1-C.sub.15)alkylaryl group; wherein n is an integer from 1-8; P(O)(OH)OP(O)(OH).sub.2. halogen, nitro, cyano, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkoxy, —N(R.sub.11a).sub.2, C.sub.1-C.sub.6 acylamino, —COR.sub.11b, —OCOR.sub.11b; NHSO.sub.2(C.sub.1-C.sub.6 alkyl), —SO.sub.2N(R.sub.11a).sub.2SO.sub.2; wherein each R.sub.11a is independently selected from H and C.sub.1-C.sub.6 alkyl, and R.sub.11b is independently selected from OH, C.sub.1-C.sub.6 alkoxy, NH.sub.2, NH(C.sub.1-C.sub.6 alkyl), and N(C.sub.1-C6 alkyl).sub.2; R.sub.12 is selected from H, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.1-C.sub.10 haloalkyl, C.sub.3-C.sub.10 cycloalkyl, C.sub.3-C.sub.10 heterocycloalkyl, C.sub.5-C.sub.18 aryl, C.sub.1-C.sub.4 alkylaryl, and C.sub.5-C.sub.12 heteroaryl; wherein the aryl or heteroaryl groups are optionally substituted with one or two groups selected from halogen, trifluoromethyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, and cyano; and R.sub.A and R.sub.A′ are independently selected from H, C.sub.1-C10 alkyl, C.sub.2-C10 alkenyl, C.sub.2-C.sub.10 alkynyl, C.sub.3-C.sub.10 cycloalkyl, C.sub.1-C10 thioalkyl, C.sub.1-C10 hydroxylalkyl, C.sub.1-C10 alkylaryl, and C.sub.5-C12 aryl, C.sub.3-C10 heterocycloalkyl, heteroaryl, —(CH.sub.2).sub.3NHC(═NH)NH.sub.2, (1H-indol-3-yl) methyl, (1H-imidazol-4-yl) methyl, and a side chain selected from a proteinogenic or non-proteinogenic amino acid; wherein the aryl groups are optionally substituted with a group selected from hydroxyl, C.sub.1-C10 alkyl, C.sub.1-C6 alkoxy, halogen, nitro, and cyano; or R.sub.9 and R.sub.10 form, together with the phosphorus atoms to which they are attached, a 6-membered cycle, wherein —R.sub.9-R.sub.10— is —CH.sub.2—CH.sub.2—CHR—; wherein R is selected from H, a (C.sub.5-C.sub.6) aryl, and a (C.sub.5-C.sub.6) heteroaryl group; wherein the aryl or heteroaryl groups are optionally substituted with halogen, trifluoromethyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C6 alkoxy, and cyano; or R.sub.9 and R.sub.10 form, together with the phosphorus atoms to which they are attached, a 6-membered cycle, wherein —R.sub.9-R.sub.10— is —O—CH.sub.2—CH.sub.2—CHR—O—; wherein R is selected from H, a (C.sub.5-C.sub.6) aryl, and a (C.sub.5-C.sub.6) heteroaryl group; wherein the aryl or heteroaryl groups are optionally substituted with halogen, trifluoromethyl, (C.sub.1-C.sub.6) alkyl, (C.sub.1-C6) alkoxy, and cyano; R.sub.8 is selected from H, OR, NHR.sub.13, NR.sub.13R.sub.14, NH—NHR.sub.13, SH, CN, N.sub.3, and halogen; wherein R.sub.13 and R.sub.14 selected, independently of one another, from H, (C.sub.1-C.sub.8) alkyl, (C.sub.1-C.sub.8) alkylaryl, and —CR.sub.BR.sub.C—C(O)—OR.sub.D; wherein R.sub.B and R.sub.C are independently a hydrogen atom, (C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy, benzyl, indolyl or imidazolyl; wherein the (C.sub.1-C.sub.6) alkyl and the (C.sub.1-C.sub.6) alkoxy may, optionally and independently of one another, be substituted by one or more halogen, amino, amido, guanidyl, hydroxyl, thiol, or carboxyl groups; and the benzyl group is optionally substituted by one or more halogen or hydroxyl groups; or R.sub.B and R.sub.C, together with the carbon atom to which they are attached, form a C.sub.3-C.sub.6 cycloalkyl group optionally substituted with one or more halogen, amino, amido, guanidyl, hydroxyl, thiol, and carboxyl; and R.sub.D is hydrogen, (C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl, (C.sub.2-C.sub.6) alkynyl, or (C.sub.3-C.sub.6) cycloalkyl; Y is selected from CH, CH.sub.2, C(CH.sub.3).sub.2, and CCH.sub.3; is a single or double bond depending on Y; and is the alpha or beta anomer depending on the position of R.sub.1 or a compound of formula (Ia): ##STR00063## or a pharmaceutically acceptable stereoisomer, salt, hydrate, solvate, or crystal thereof, or a combination thereof, wherein X′.sub.1 and X′.sub.2 are independently selected from O, CH.sub.2, S, Se, CHF, CF.sub.2, and C═CH.sub.2; R′.sub.1 and R′13 are independently selected from H, azido, cyano, C1-C8 alkyl, C1-C8 thioalkyl, C1-C8 heteroalkyl, and OR; wherein R is selected from H and C.sub.1-C8 alkyl; R′.sub.2, R′.sub.3, R′.sub.4, R′.sub.5, R′.sub.9, R′.sub.10, R′.sub.11, R′.sub.12 are independently selected from H, halogen, azido, cyano, hydroxyl, C.sub.1-C.sub.12 alkyl, C.sub.1-C.sub.12 thioalkyl, C.sub.1-C.sub.12 heteroalkyl, C.sub.1-C.sub.12 haloalkyl, and OR; wherein R may be selected from H, C.sub.1-C.sub.12 alkyl, C(O)(C.sub.1-C.sub.12) alkyl, C(O)NH(C.sub.1-C.sub.12) alkyl, C(O)O(C.sub.1-C.sub.12) alkyl, C(O) aryl, C(O)(C.sub.1-C.sub.12) alkylaryl, C(O)(C.sub.1-C.sub.12) aryl, C(O)NH(C.sub.1-C.sub.12) alkylaryl, C(O)O(C.sub.1-C.sub.12) alkylaryl, and a C(O)CHR.sub.AANH.sub.2 group; wherein R.sub.AA is a side chain selected from the proteinogenic amino acids; R′.sub.6 and R′.sub.8 are independently selected from H, azido, cyano, C.sub.1-C.sub.8 alkyl, and OR, wherein R is selected from H and C.sub.1-C.sub.8 alkyl; R′.sub.7 and R′.sub.14 are independently selected from H, OR, NHR, NRR′, NH—NHR, SH, CN, N.sub.3, and halogen; wherein R and R′ are independently selected from H and (C.sub.1-C.sub.8) alkylaryl; Y′1 and Y′2 are independently selected from CH, CH.sub.2, C(CH.sub.3).sub.2 and CCH.sub.3; M′ is selected from H and a suitable counterion; is a single or double bond, depending on Y′1 and Y′2; and is an alpha or beta anomer depending on the position of R′.sub.1 and R′.sub.13; and combinations thereof, for use in the prevention and/or treatment of ankylosing spondylitis.

2. Compound of formula (I) for use according to claim 1, selected from compound I-A, compound I-B, compound I-C, compound I-D, compound I-E, compound I-F, compound I-G, compound I-H, compound I-I, compound I-J, preferably compound I-C, compound I-D, or compound I-F, preferably compound IB, compound IC, compound ID, compound IF, and combinations thereof, preferably from compound IB, compound IC, compound ID, compound IF, and combinations thereof.

3. Compound of formula (Ia) for use according to claim 1, selected from compounds Ia-A to Ia-I, preferably from the compound of formula Ia-B, the compound of formula Ia-C, the compound of formula Ia-E, the compound of formula Ia-F, the compound of formula Ia-H, the compound of formula Ia-I, and the compound of formula Ia-G.

4. Compound of formula (I) or (Ia) for use according to claim 1, administered orally, intraocularly, sublingually, intravenously, intramuscularly, intraarticularly, subcutaneously, transcutaneously, vaginally, peridurally, intravesically, rectally, or by inhalation.

5. Compound of formula (I) or (Ia) for use according to claim 1 in combination with at least one additional therapeutic agent.

6. Compound of formula (I) or (Ia) for use according to claim 5, wherein the at least one additional therapeutic agent is an analgesic, an NSAID, cortisone, a cortisone derivative, an immunosuppressant, an immunomodulator, an anti-TNF agent, an anti-interleukin agent, and combinations thereof.

7. Compound of formula (I) or (Ia) for use according to claim 6, wherein the at least one additional therapeutic agent is an immunosuppressant selected from methotrexate and cyclosporine, preferably methotrexate.

8. Composition comprising a compound of formula (I): ##STR00064## or a pharmaceutically acceptable stereoisomer, salt, hydrate, solvate, or crystal thereof, wherein X is selected from O, CH.sub.2, S, Se, CHF, CF.sub.2, C═CH.sub.2; R.sub.1 is selected from H, azido, cyano, C.sub.1-C8 alkyl, C.sub.1-C8 thioalkyl, C.sub.1-C8 heteroalkyl, and OR; wherein R is selected from H and C.sub.1-C8 alkyl; R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are selected independently of one another from H, halogen, azido, cyano, hydroxyl, C.sub.1-C12 alkyl, C.sub.1-C12 thioalkyl, C.sub.1-C12 heteroalkyl, C.sub.1-C12 haloalkyl, and OR; wherein R is selected from H, C.sub.1-C.sub.12 alkyl, C(O)(C.sub.1-C.sub.12) alkyl, C(O)NH(C.sub.1-C.sub.12) alkyl, C(O)O(C.sub.1-C.sub.12) alkyl, C(O) aryl, C(O)(C.sub.1-C.sub.12) alkylaryl, C(O)NH(C.sub.1-C.sub.12) alkylaryl, C(O)O(C.sub.1-C.sub.12) alkylaryl, and C(O)CHR.sub.AANH.sub.2; wherein R.sub.AA is a side chain selected from the proteinogenic amino acids; R.sub.6 is selected from H, azido, cyano, C.sub.1-C8 alkyl, C.sub.1-C8 thioalkyl, C.sub.1-C8 heteroalkyl, and OR; wherein R is selected from H and C.sub.1-C8 alkyl; R.sub.7 is selected from H, P(O)R.sub.9R.sub.10, and P(S)R.sub.9R.sub.10; wherein R.sub.9 and R.sub.10 are selected independently of one another from OH, OR.sub.11, NHR.sub.13, NR.sub.13R.sub.14, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C10 cycloalkyl, C.sub.5-C12 aryl, (C.sub.1-C.sub.8) alkylaryl, (C.sub.1-C.sub.8) arylalkyl, (C.sub.1-C.sub.8) heteroalkyl, (C.sub.1-C.sub.8) heterocycloalkyl, heteroaryl, and NHCHR.sub.AR.sub.A′C(O)R.sub.12; wherein: R.sub.11 is selected from a C.sub.1-C10 alkyl, C.sub.3-C10 cycloalkyl, C.sub.5-C18 aryl, C.sub.1-C10 alkylaryl, substituted C.sub.5-C12 aryl, C.sub.1-C10 heteroalkyl, C.sub.3-C10 heterocycloalkyl, C.sub.1-C.sub.10 haloalkyl, heteroaryl, —(CH.sub.2).sub.nC(O)(C.sub.1-C.sub.15) alkyl, —(CH.sub.2).sub.nOC(O)(C.sub.1-C.sub.15) alkyl, —(CH.sub.2).sub.nOC(O)O(C.sub.1-C.sub.15) alkyl, —(CH.sub.2).sub.nSC(O)(C.sub.1-C.sub.15) alkyl, —(CH.sub.2).sub.nC(O)O(C.sub.1-C.sub.15) alkyl, and —(CH.sub.2).sub.nC(O)O(C.sub.1-C.sub.15)alkylaryl group; wherein n is an integer from 1-8; P(O)(OH)OP(O)(OH).sub.2. halogen, nitro, cyano, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkoxy, —N(R.sub.11a).sub.2, C.sub.1-C.sub.6 acylamino, —COR.sub.11b, —OCOR.sub.11b; NHSO.sub.2(C.sub.1-C6 alkyl), —SO.sub.2N(R.sub.11a).sub.2SO.sub.2; wherein each R.sub.11a is independently selected from H and C.sub.1-C.sub.6 alkyl, and R.sub.11b is independently selected from OH, C.sub.1-C.sub.6 alkoxy, NH.sub.2, NH(C.sub.1-C.sub.6 alkyl), and N(C.sub.1-C.sub.6 alkyl).sub.2; R.sub.12 is selected from H, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.1-C.sub.10 haloalkyl, C.sub.3-C.sub.10 cycloalkyl, C.sub.3-C.sub.10 heterocycloalkyl, C.sub.5-C.sub.18 aryl, C.sub.1-C.sub.4 alkylaryl, and C.sub.5-C.sub.12 heteroaryl; wherein the aryl or heteroaryl groups are optionally substituted with one or two groups selected from halogen, trifluoromethyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, and cyano; and R.sub.A and R.sub.A′ are independently selected from H, C.sub.1-C10 alkyl, C.sub.2-C10 alkenyl, C.sub.2-C.sub.10 alkynyl, C.sub.3-C.sub.10 cycloalkyl, C.sub.1-C10 thioalkyl, C.sub.1-C10 hydroxylalkyl, C.sub.1-C10 alkylaryl, and C.sub.5-C12 aryl, C.sub.3-C10 heterocycloalkyl, heteroaryl, —(CH.sub.2).sub.3NHC(═NH)NH.sub.2, (1H-indol-3-yl) methyl, (1H-imidazol-4-yl) methyl, and a side chain selected from a proteinogenic or non-proteinogenic amino acid; wherein the aryl groups are optionally substituted with a group selected from hydroxyl, C.sub.1-C10 alkyl, C.sub.1-C6 alkoxy, halogen, nitro, and cyano; or R.sub.9 and R.sub.10 form, together with the phosphorus atoms to which they are attached, a 6-membered cycle, wherein —R.sub.9-R.sub.10— is —CH.sub.2—CH.sub.2—CHR—; wherein R is selected from H, a (C.sub.5-C.sub.6) aryl, and a (C.sub.5-C.sub.6) heteroaryl group; wherein the aryl or heteroaryl groups are optionally substituted with halogen, trifluoromethyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C6 alkoxy, and cyano; or R.sub.9 and R.sub.10 form, together with the phosphorus atoms to which they are attached, a 6-membered cycle, wherein —R.sub.9-R.sub.10— is —O—CH.sub.2—CH.sub.2—CHR—O—; wherein R is selected from H, a (C.sub.5-C.sub.6) aryl, and a (C.sub.5-C.sub.6) heteroaryl group; wherein the aryl or heteroaryl groups are optionally substituted with halogen, trifluoromethyl, (C.sub.1-C.sub.6) alkyl, (C.sub.1-C6) alkoxy, and cyano; R.sub.8 is selected from H, OR, NHR.sub.13, NR.sub.13R.sub.14, NH—NHR.sub.13, SH, CN, N.sub.3, and halogen; wherein R.sub.13 and R.sub.14 selected, independently of one another, from H, (C.sub.1-C.sub.8) alkyl, (C.sub.1-C.sub.8) alkylaryl, and —CR.sub.BR.sub.C—C(O)—OR.sub.D; wherein R.sub.B and R.sub.C are independently a hydrogen atom, (C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy, benzyl, indolyl or imidazolyl; wherein the (C.sub.1-C.sub.6) alkyl and the (C.sub.1-C.sub.6) alkoxy may, optionally and independently of one another, be substituted by one or more halogen, amino, amido, guanidyl, hydroxyl, thiol, or carboxyl groups; and the benzyl group is optionally substituted by one or more halogen or hydroxyl groups; or R.sub.B and R.sub.C, together with the carbon atom to which they are attached, form a C.sub.3-C.sub.6 cycloalkyl group optionally substituted with one or more halogen, amino, amido, guanidyl, hydroxyl, thiol, and carboxyl; and R.sub.D is hydrogen, (C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl, (C.sub.2-C.sub.6) alkynyl, or (C.sub.3-C.sub.6) cycloalkyl; Y is selected from CH, CH.sub.2, C(CH.sub.3).sub.2, and CCH.sub.3; is a single or double bond depending on Y; and is the alpha or beta anomer depending on the position of R.sub.1 and/or a compound of formula (Ia): ##STR00065## or a pharmaceutically acceptable stereoisomer, salt, hydrate, solvate, or crystal thereof, or a combination thereof, wherein X′.sub.1 and X′.sub.2 are independently selected from O, CH.sub.2, S, Se, CHF, CF.sub.2, and C═CH.sub.2; R′.sub.1 and R′13 are independently selected from H, azido, cyano, C1-C8 alkyl, C1-C8 thioalkyl, C1-C8 heteroalkyl, and OR; wherein R is selected from H and C.sub.1-C8 alkyl; R′.sub.2, R′.sub.3, R′.sub.4, R′.sub.5, R′.sub.9, R′.sub.10, R′.sub.11, R′.sub.12 are independently selected from H, halogen, azido, cyano, hydroxyl, C.sub.1-C.sub.12 alkyl, C.sub.1-C.sub.12 thioalkyl, C.sub.1-C.sub.12 heteroalkyl, C.sub.1-C.sub.12 haloalkyl, and OR; wherein R may be selected from H, C.sub.1-C.sub.12 alkyl, C(O)(C.sub.1-C.sub.12) alkyl, C(O)NH(C.sub.1-C.sub.12) alkyl, C(O)O(C.sub.1-C.sub.12) alkyl, C(O) aryl, C(O)(C.sub.1-C.sub.12) alkylaryl, C(O)(C.sub.1-C.sub.12) aryl, C(O)NH(C.sub.1-C.sub.12) alkylaryl, C(O)O(C.sub.1-C.sub.12) alkylaryl, and a C(O)CHR.sub.AANH.sub.2 group; wherein R.sub.AA is a side chain selected from the proteinogenic amino acids; R′.sub.6 and R′.sub.8 are independently selected from H, azido, cyano, C.sub.1-C.sub.8 alkyl, and OR, wherein R is selected from H and C.sub.1-C.sub.8 alkyl; R′.sub.7 and R′.sub.14 are independently selected from H, OR, NHR, NRR′, NH—NHR, SH, CN, N.sub.3, and halogen; wherein R and R′ are independently selected from H and (C.sub.1-C.sub.8) alkylaryl; Y′1 and Y′2 are independently selected from CH, CH.sub.2, C(CH.sub.3).sub.2 and CCH.sub.3; M′ is selected from H and a suitable counterion; is a single or double bond, depending on Y′1 and Y2; and is an alpha or beta anomer depending on the position of R′.sub.1 and R′.sub.13; and at least one pharmaceutically acceptable excipient for use in the prevention and/or treatment of ankylosing spondylitis.

9. Composition according to claim 8, further comprising at least one additional therapeutic agent.

10. Compound according to claim 9, wherein the at least one additional therapeutic agent is selected from an analgesic, an NSAID, cortisone, a cortisone derivative, an immunosuppressant, an immunomodulator, an anti-TNF agent, an anti-interleukin agent, and combinations thereof.

11. Composition according to claim 8, wherein it is administered orally, intraocularly, sublingually, intravenously, intraarterially, intramuscularly, intraarticularly, subcutaneously, transcutaneously, vaginally, peridurally, intravesically, rectally, or by inhalation

12. Composition according to claim 11, wherein it may be administered in the form of a sublingual tablet or a gastroresistant capsule.

13. Composition according to claim 8, wherein the compound of formula (I) is selected from compound I-A, compound I-B, compound I-C, compound I-D, compound I-E, compound I-F, compound I-G, compound I-H, compound I-I, compound I-J, preferably compound I-C, compound I-D, or compound I-F.

14. Composition according to claim 8, wherein the compound of formula (Ia) is selected from the compound of formula Ia-B, the compound of, wherein the compound of formula I is selected from the compound of formula Ia-C, the compound of formula Ia-E, the compound of formula Ia-F, the compound of formula Ia-H, the compound of formula Ia-I, and the compound of formula Ia-G, and combinations thereof.

15. Combination preparation comprising a compound of formula (I) and/or a compound of formula (Ia) according to claim 1, and/or a composition comprising the compound of formula (I) and/or the compound of formula (Ia) and at least one additional therapeutic agent for use in the prevention and/or treatment of ankylosing spondylitis.

Description

FIGURES

[0281] FIG. 1 is a graph of the development of the average weight of mice as a function of treatments.

[0282] FIG. 2 is a graph of the development of the average joint score as a function of treatments.

[0283] FIG. 3 is a graph of the development of the average tail score as a function of treatments.

EXAMPLE

[0284] In the following, the examples are provided solely to illustrate this invention, and by no means to limit its scope.

[0285] The efficacy of the use of NMN (compound IE) according to the invention was evaluated in 3-week-old TgA86 mice as a model for ankylosing spondylitis. TgA86 mice develop peripheral and axial AS with an incidence of 100%. In these mice, the peripheral form is manifested by joint welling and paw deformation, whilst the axial form is clinically characterised by curved tails and pelvic ankylosis.

[0286] In brief, male TgA86 mice were divided into two groups of 10 mice each: (i) a control group, in which the mice were treated with vehicle, i.e. a 0.9% NaCl solution (10 mL/kg), marked ‘Vehicle’; (iv) a group of mice treated with NMN (185 mg/kg), marked ‘NMN’. The solutions were injected intraperitoneally.

[0287] The mice were treated for 10 weeks under the conditions set forth supra. The joint score, tail score, and weight of the mice were measured every week. The joint score was determined in accordance with table 3 infra:

TABLE-US-00007 TABLE 3 Peripheral pathology Joint score Interpretation Parameters 0 No disease No arthritis (normal appearance, mouse can support its weight by clinging to an inverted or inclined surface such as a wire rack or a cage cover for a certain amount of time, maximum grip force). 0.5 Mild disease Appearance of arthritis: Mild joint swelling, all other parameters as with a score of 0. 1 Mild-to-moderate Joint deformation due to swelling, disease paw inflammation, all other parameters as with a score of 1. 1.5 Moderate disease Paw joint swelling, deformation + inward deformation of the last digit, brief support when mouse clings to an inverted or inclined surface such as a wire rack or a cage cover, reduced grip force. 2 Moderate-to-severe Significant swelling of paw joint and disease digits, deformation of leg joint, deformation, no support when clinging to an inverted or inclined surface such as a wire rack or a cage cover, no grip force, climbing/feeding affected.

[0288] The tail score is an indicator that allows for an evaluation of the axial form of AS and pelvic ankylosis (see https://www.biomedcode.com/wp-content/uploads/2019/07/TgA86-white-paper.pdf). The tail score was determined in accordance with table 4 infra:

TABLE-US-00008 TABLE 4 Axial pathology Tail score Interpretation Parameters 0 No disease Normal. Normal tail phenotype. 1 Moderate disease Normal tail with first signs of tail flexion (mild flexion in one or more places). 2 Moderate-to-severe Multiple mild-to-severe tail flexions disease (tight flexions). 3 Severe disease Tail ankylosis with severe, tight tail flexions.

[0289] The significance of the values analysed with the Student test (T-test) are indicated as indicated in table 5:

TABLE-US-00009 TABLE 5 Symbol T-test > 0.1 * T-test > 0.05 **

[0290] As can be seen in FIG. 1, the weight of the mice treated with NMN follows a similar course of development to that of the control group. The decrease observed is not significant. This result shows that NMN is well tolerated by the mice and does not cause any distress or toxicity in the animals. Thus, the administration of NMN is safe.

[0291] As can be seen in FIG. 2, the administration of NMN allows for a reduction in the joint score of the mice compared to the control group, i.e. the administration of NMN reduces joint inflammation in this model of peripheral AS. Moreover, the reduction is particularly significant starting in the 5.sup.th week of treatment, thus showing the efficacy of treatment with NMN for joint swelling induced by AS.

[0292] FIG. 3 shows the development of the tail score, which allows for a determination of whether the axial form of AS is improving or worsening in this mouse model. As can be seen, the administration of NMN reduces the tail score in the mice treated compared to the control group; i.e. the spinal column of the mice is less deformed and the pelvis less ankylosed. The reduction is significant starting in the second week of treatment. As such, NMN is effective to treat the axial form of AS.

[0293] The compounds of formula (I) or (Ia), as well as compositions comprising them, can thus be used safely and successfully to treat and prevent ankylosing spondylitis. Thus, this invention provides a therapeutic alternative to conventional treatments for AS, or at least proposes a therapeutic adjunct to conventional treatments in order to reduce their frequency and dosage. Given the safety of the compounds according to the invention, as well as the compositions comprising them, this invention is capable of treating and/or preventing AS without inducing the side-effects caused by conventional treatments.