Search

EP-3448381-B1 - ANTAGONISTS OF THE THYROID-STIMULATING HORMONE RECEPTOR (TSHR)

EP3448381B1EP 3448381 B1EP3448381 B1EP 3448381B1EP-3448381-B1

Inventors

  • KRAUSE, GERD
  • HOYER, Inna
  • SPECKER, EDGAR
  • FURKERT, Jens
  • MARCINKOWSKI, Patrick
  • VON KRIES, JENS-PETER
  • NEUENSCHWANDER, MARTIN
  • NAZARE, MARC

Dates

Publication Date
20260506
Application Date
20170426

Claims (15)

  1. Compound according to Formula I for use in the treatment of hyperthyroidism, wherein - R 1 = H, OH, alkyl, alkoxy, carbonyl, alkoxycarbonyl, NH 2 , halogen, an optionally substituted 6-member ring, preferably an aryl group, such as phenyl, wherein said optional substituent is selected from the group consisting of OH, alkyl, alkoxy, carbonyl, alkoxycarbonyl, NO 2 , amine, halogen, CX 3 , wherein X is a halogen, or wherein wherein R 1b = alkyl, an optionally substituted 6-member ring, preferably an aryl group, such as phenyl, wherein said optional substituent is selected from the group consisting of OH, alkyl, alkoxy, carbonyl, alkoxycarbonyl, NO 2 , amine, halogen, CX 3 , wherein X is a halogen; - R 2 = H, OH, alkyl, halogen-substituted alkyl, alkoxy, carbonyl, alkoxycarbonyl, NO 2 , amine, aminocarbonyl; - R 3 = H, OH, alkyl, alkoxy, carbonyl, alkoxycarbonyl, halogen; - R 4 , R 5 = H, alkyl, alkoxy, carbonyl, alkoxycarbonyl, wherein R 4 and R 5 can be the same or different, or wherein R 4 and R 5 = wherein R 6 = H, OH, alkyl, alkoxy, carbonyl, alkoxycarbonyl, NO 2 , amine, aminocarbonyl, halogen, CX 3 , wherein X is a halogen.
  2. Compound for use according to claim 1, according to Formula I - wherein R 1 to R 3 are as in claim 1, - and wherein R 4 and R 5 = - wherein R 6 = H, OH, alkyl, alkoxy, carbonyl, alkoxycarbonyl, NO 2 , amine, aminocarbonyl, halogen, CX 3 , wherein X is a halogen.
  3. Compound for use according to claim 1, according to Formula I, wherein - R 1 = H, OH, alkyl, O-alkyl, CO-alkyl, C(O)O-alkyl, NH 2 , halogen, preferably F, an optionally substituted 6-member ring, preferably phenyl, wherein said optional substituent is selected from the group consisting of OH, alkyl, O-alkyl, CO-alkyl, C(O)O-alkyl, NO 2 , NH 2 , halogen, CX 3 , wherein X is halogen, or wherein wherein R 1b = alkyl, an optionally substituted 6-member ring, preferably phenyl, wherein said optional substituent is selected from the group consisting of OH, alkyl, O-alkyl, CO-alkyl, C(O)O-alkyl, NO 2 , NH 2 , halogen, CX 3 , wherein X is a halogen, preferably F; - R 2 = H, OH, alkyl, halogen-substituted alkyl, O-alkyl, CO-alkyl, C(O)O-alkyl, NO 2 , NH 2 , NHR 2a , NHR 2a R 2b , NHCOR 2c , wherein R 2a , R 2b , R 2c is alkyl; - R 3 = H, OH, alkyl, O-alkyl, C(O)O-alkyl, halogen; - R 4 , R 5 = H, alkyl, wherein R 4 and R 5 can be the same or different, or wherein R 4 and R 5 = wherein R 6 = H, OH, alkyl, O-alkyl, CO-alkyl, C(O)O-alkyl, NO 2 , NH 2 , NHR 2a , NHR 2a R 2b , NHCOR 2c , wherein R 2a , R 2b , R 2c is alkyl, X, CX 3 , wherein X is a halogen, preferably F; and wherein any one or more of said alkyl groups is straight-chained or branched, preferably C1-C6, more preferably Me or Et.
  4. Compound for use according to claim 3, according to Formula I - wherein R 1 to R 3 are as in claim 3, - and wherein R 4 and R 5 = - wherein R 6 = H, OH, alkyl, O-alkyl, CO-alkyl, C(O)O-alkyl, NO 2 , NH 2 , NHR 2a , NHR 2a R 2b , NHCOR 2c , wherein R 2a , R 2b , R 2c is alkyl, X, CX 3 , wherein X is a halogen, preferably F; and wherein any one or more of said alkyl groups is straight-chained or branched, preferably C1-C6, more preferably Me or Et.
  5. Compound for use according to any one of the preceding claims, according to Formula II and/or enantiomers of structures according to Formula II, wherein - R 1 = H, OH, alkyl, alkoxy, carbonyl, alkoxycarbonyl, NH 2 , halogen, an optionally substituted 6-member ring, preferably an aryl group, such as phenyl, wherein said optional substituent is selected from the group consisting of OH, alkyl, alkoxy, carbonyl, alkoxycarbonyl, NO 2 , amine, halogen, CX 3 , wherein X is a halogen, or wherein wherein R 1b = alkyl, an optionally substituted 6-member ring, preferably an aryl group, such as phenyl, wherein said optional substituent is selected from the group consisting of OH, alkyl, alkoxy, carbonyl, alkoxycarbonyl, NO 2 , amine, halogen, CX 3 , wherein X is a halogen; - R 2 = H, OH, alkyl, halogen-substituted alkyl, alkoxy, carbonyl, alkoxycarbonyl, NO 2 , amine, aminocarbonyl; - R 3 = H, OH, alkyl, alkoxy, carbonyl, alkoxycarbonyl, halogen; - R 6 = H, OH, alkyl, alkoxy, carbonyl, alkoxycarbonyl, NO 2 , amine, aminocarbonyl, halogen, CX 3 , wherein X is a halogen.
  6. Compound for use according to claim 5, according to Formula III wherein - R 1 = H, OH, alkyl, alkoxy, carbonyl, alkoxycarbonyl, NH 2 , halogen, an optionally substituted 6-member ring, preferably an aryl group, such as phenyl, wherein said optional substituent is selected from the group consisting of OH, alkyl, alkoxy, carbonyl, alkoxycarbonyl, NO 2 , amine, halogen, CX 3 , wherein X is a halogen, or wherein wherein R 1b = alkyl, an optionally substituted 6-member ring, preferably an aryl group, such as phenyl, wherein said optional substituent is selected from the group consisting of OH, alkyl, alkoxy, carbonyl, alkoxycarbonyl, NO 2 , amine, halogen, CX 3 , wherein X is a halogen; - R 2 = H, OH, alkyl, halogen-substituted alkyl, alkoxy, carbonyl, alkoxycarbonyl, NO 2 , amine, aminocarbonyl; - R 3 = H, OH, alkyl, alkoxy, carbonyl, alkoxycarbonyl, halogen; - R 6 = H, OH, alkyl, alkoxy, carbonyl, alkoxycarbonyl, NO 2 , amine, aminocarbonyl, halogen, CX 3 , wherein X is a halogen.
  7. Compound for use according to any one of the preceding claims, according to Formula II and/or enantiomers of structures according to Formula II, wherein - R 1 = H, OH, alkyl, O-alkyl, CO-alkyl, C(O)O-alkyl, NH 2 , halogen, preferably F, an optionally substituted 6-member ring, preferably phenyl, wherein said optional substituent is selected from the group consisting of OH, alkyl, O-alkyl, CO-alkyl, C(O)O-alkyl, NO 2 , NH 2 , halogen, CX 3 , wherein X is halogen, or wherein wherein R 1b = alkyl, an optionally substituted 6-member ring, preferably phenyl, wherein said optional substituent is selected from the group consisting of OH, alkyl, O-alkyl, CO-alkyl, C(O)O-alkyl, NO 2 , NH 2 , halogen, CX 3 , wherein X is a halogen, preferably F; - R 2 = H, OH, alkyl, halogen-substituted alkyl, O-alkyl, CO-alkyl, C(O)O-alkyl, NO 2 , NH 2 , NHR 2a , NHR 2a R 2b , NHCOR 2c , wherein R 2a , R 2b , R 2c is alkyl; - R 3 = H, OH, alkyl, O-alkyl, C(O)O-alkyl, halogen; - R 6 = H, OH, alkyl, O-alkyl, CO-alkyl, C(O)O-alkyl, NO 2 , NH 2 , NHR 2a , NHR 2a R 2b , NHCOR 2c , wherein R 2a , R 2b , R 2c is alkyl, halogen, CX 3 , wherein X is a halogen, preferably F; and wherein any one or more of said alkyl groups is straight-chained or branched, preferably C1-C6, more preferably Me or Et.
  8. Compound for use according to any one of the preceding claims, according to Formula III - R 1 = H, OH, alkyl, O-alkyl, CO-alkyl, C(O)O-alkyl, NH 2 , halogen, preferably F, an optionally substituted 6-member ring, preferably phenyl, wherein said optional substituent is selected from the group consisting of OH, alkyl, O-alkyl, CO-alkyl, C(O)O-alkyl, NO 2 , NH 2 , halogen, CX 3 , wherein X is halogen, or wherein wherein R 1b = alkyl, an optionally substituted 6-member ring, preferably phenyl, wherein said optional substituent is selected from the group consisting of OH, alkyl, O-alkyl, CO-alkyl, C(O)O-alkyl, NO 2 , NH 2 , halogen, CX 3 , wherein X is a halogen, preferably F; - R 2 = H, OH, alkyl, halogen-substituted alkyl, O-alkyl, CO-alkyl, C(O)O-alkyl, NO 2 , NH 2 , NHR 2a , NHR 2a R 2b , NHCOR 2c , wherein R 2a , R 2b , R 2c is alkyl; - R 3 = H, OH, alkyl, O-alkyl, C(O)O-alkyl, halogen; - R 6 = H, OH, alkyl, O-alkyl, CO-alkyl, C(O)O-alkyl, NO 2 , NH 2 , NHR 2a , NHR 2a R 2b , NHCOR 2c , wherein R 2a , R 2b , R 2c is alkyl, halogen, CX 3 , wherein X is a halogen, preferably F; and wherein any one or more of said alkyl groups is straight-chained or branched, preferably C1-C6, more preferably Me or Et.
  9. Compound for use according to claim 1, according to Formula I wherein wherein R 1b = alkyl, an optionally substituted 6-member ring, preferably an aryl group, such as phenyl, wherein said optional substituent is selected from the group consisting of OH, alkyl, alkoxy, carbonyl, alkoxycarbonyl, NO 2 , amine, halogen, CX 3 , wherein X is a halogen; - R 2 = H, OH, alkyl, halogen-substituted alkyl, alkoxy, carbonyl, alkoxycarbonyl, NO 2 , amine, aminocarbonyl; - R 3 = H, OH, alkyl, alkoxy, carbonyl, alkoxycarbonyl, halogen; - R 4 , R 5 = H, alkyl, alkoxy, carbonyl, alkoxycarbonyl preferably wherein - R 1b = Me, C(O)O(CH 2 ) 2 CH 3 , phenyl, or substituted phenyl comprising a CF 3 group; - R 2 = H, Me, NO 2 , NH 2 ; - R 3 = H, OH, Me, O-Me, C(O)O-Me; - R 4 , R 5 = H.
  10. Compound for use according to claim 1 or 9, according to Formula I wherein wherein R 1b = alkyl, an optionally substituted 6-member ring, preferably phenyl, wherein said optional substituent is selected from the group consisting of OH, alkyl, O-alkyl, CO-alkyl, C(O)O-alkyl, NO 2 , NH 2 , halogen, CX 3 , wherein X is a halogen, preferably F; - R 2 = H, OH, alkyl, halogen-substituted alkyl, O-alkyl, CO-alkyl, C(O)O-alkyl, NO 2 , NH 2 , NHR 2a , NHR 2a R 2b , NHCOR 2c , wherein R 2a , R 2b , R 2c is alkyl; - R 3 = H, OH, alkyl, O-alkyl, C(O)O-alkyl, halogen; - R 4 , R 5 = H, alkyl; and wherein any one or more of said alkyl groups is straight-chained or branched, preferably C1-C6, more preferably Me or Et, preferably wherein - R 1b = Me, C(O)O(CH 2 ) 2 CH 3 , phenyl, or substituted phenyl comprising a CF 3 group; - R 2 = H, Me, NO 2 , NH 2 ; - R 3 = H, OH, Me, O-Me, C(O)O-Me; - R 4 , R 5 = H.
  11. Compound for use according to claims 3 to 8, according to Formula II or III, wherein - R 1 = H, OH, Me, O-Me, CO-Me, C(O)O-Me, NH 2 , halogen, phenyl, or substituted phenyl comprising a C(O)O-Me group, or wherein wherein R 1b = Me, phenyl; - R 2 = H, Me, NO 2 , NH 2 ; - R 3 = H, OH, Me, O-Me, C(O)O-Me; - R 6 = H, OH, Me, O-Me, CO-Me, C(O)O-Me, N(CH 3 ) 2 , F, CF 3 .
  12. Compound for use according to claim 1, according to Formula I, wherein the compound is
  13. Compound for use according to any one of the preceding claims, according to Formula I, II or III, wherein the compound is selected from the group comprising:
  14. Compound for use according to any one of the preceding claims, wherein the hyperthyroidism is Graves' disease, Graves' ophthalmopathy and/or Graves' dermopathy, or wherein the hyperthyroidism occurs in a subject with thyroid cancer.
  15. Pharmaceutical composition for use in the treatment of hyperthyroidism, said composition comprising a compound according to any one of the preceding claims and a pharmaceutically acceptable carrier substance.

Description

The invention relates to chemical compounds that are useful in the treatment of hyperthyroidism, in particular to compounds that exhibit activity as thyroid-stimulating hormone receptor (TSHR) antagonists and their use in the treatment of hyperthyroidism, also wherein the hyperthyroidism is Graves' disease, Graves' Ophthalmopathy and wherein the hyperthyroidism occurs in a subject with thyroid cancer. BACKGROUND OF THE INVENTION About 40 % of hyperthyroidism patients suffer from Graves' disease (Morbus Basedow), an autoimmune disease in which autoantibodies activate the thyrotropin receptor, mimicking its natural hormone ligand, the thyroid-stimulating hormone (TSH). This pathological activation of TSH-Receptor (TSHR) leads to uncontrolled production of thyroid hormones causing hyperthyroidism. TSH and the TSHR are key proteins in the control of thyroid function. In fact, TSHR is mainly expressed in follicular epithelial cells of the thyroid gland, but also in a variety of additional cell types such as retro-orbital fibroblasts, kidney, adipocytes and bone cells. TSH binds to its receptor and leads to the stimulation of second messenger pathways involving predominantly cAMP. Inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG) pathways are also activated at higher TSH concentrations. The treatment of choice applied in the clinics for decades involves thyrostatic drugs blocking the production of thyroid hormones (TH). This medication plays a role further downstream in the signal cascade of the thyroid upon activation of the TSHR. Since thyroid hormones T3, T4 are secreted in the thyroid gland and these medications induce an inhibition of their synthesis. Thus, the current primary anti-thyroid treatment does not target the causative molecular activation of the TSHR by antibodies and patients are therefore burdened by a rate of at least 5% adverse effects (Sato et al. 2014). This demands frequent controls of the thyroid hormone levels and adjustments of thyrostatics dosage. In contrast to these drugs, which regulate the thyroid hormone level, the most promising target is the TSHR itself. However, small allosteric antagonists acting directly at the TSHR are not available on the market yet. Therapeutic gap for Graves' ophthalmopathy Moreover, about 25% of Graves' disease patients also develop an orbitopathy referred to as "Graves' Ophthalmopathy" (GO), a related organ-specific autoimmune disease affecting the appearance and functioning of the eyes. Progression to severe forms occurs rarely, no more than 3% to 6% of cases, however available therapies (Eckstein et al. 2012) are largely imperfect and remain still a dilemma (Bartalena 2011). There is considerable evidence that expression of the TSHR in the orbital fibroblasts (OF) and orbital adipocytes behind the eye may contribute to this difficult-to-treat orbitopathy, and thyroid stimulating antibodies titer tend to correlate with severity of GO. Orbital fibroblast have been recognized as primary target cells of autoimmune attack and TSHR acts as a primary autoantigen in GO. The pathological activation of TSHR leads to the production of the extracellular matrix by involvement of hyaluronan acid (HA), fibrosis and swelling of extraocular muscle as well as adipogenesis of orbital fibroblasts (orbital fat expansion) (Sorisky et al. 1996; Feliciello et al. 1993). The increase in tissue volume in the orbit often causes diplopia and compression of the optic nerve and exophthalmos. Human retroocular fibroblasts have been utilized as in vitro models to study GO. Apart from glucocorticoids and the IGF-1 receptor, which is also considered as antigen in GO, the TSHR is reckoned to be a potential target for pharmacological intervention of GO which is due to the following facts: TSHR expression is increased with adipogenesis, the TSAb (M22) itself enhances adipogenesis, it has been shown that the TSHR is linked with the HA production, since the M22 stimulated HA synthesis can be inhibited by a PI3K inhibitor or by an inhibitor of mTOR, and different TRAb induce divergent signaling pathways downstream of the TSHR such as c-Raf-ERK via Gq as unique cascade, which is not activated by TSH, which primarily activates Gs. Taken together autoimmune autoantibodies are activating TSHR in the orbita as well, but in contrast to the thyroid different molecular mechanisms are activated. Therefore, the anti-thyroid drugs available on the market blocking the thyroid hormone synthesis in the thyroid are non-effective for treatment of thyroid eye disease. This unveils the therapeutic gap for the treatment of severe GO patients in the clinics. This apparent problem has been repeatedly expressed at the annual international congresses of the European Thyroid Association (Bartalena 2013). Pharmacological approaches to tackle Graves' Ophthalmopathy A potential approach for the therapy of GO could be the suppression of the pathological activation caused by autoantibodies directly on the TSHR