Europäisches Patentamt *EP001002802B1* (19) European Patent Office Office européen des brevets (11) EP 1 002 802 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.7: C07K 5/03, C07K 5/062, of the grant of the patent: A01K 67/00, A61K 38/05, 08.12.2004 Bulletin 2004/50 A61K 38/06, A61P 5/06 (21) Application number: 99309036.4 (22) Date of filing: 12.11.1999 (54) Dipeptide derivatives as growth hormone secretagogues Dipeptide zur Förderung der Sekretion des Wachstumshormons Dipéptides comme secretagogues d’hormone de croissance (84) Designated Contracting States: (74) Representative: AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU Simpson, Alison Elizabeth Fraser et al MC NL PT SE Urquhart-Dykes & Lord LLP 30 Welbeck Street (30) Priority: 20.11.1998 US 109219 P London W1G 8ER (GB) (43) Date of publication of application: (56) References cited: 24.05.2000 Bulletin 2000/21 WO-A-96/35713 WO-A-96/38471 WO-A-97/24369 WO-A-98/58947 (73) Proprietor: Pfizer Products Inc. Groton, Connecticut 06340 (US) Remarks: The file contains technical information submitted (72) Inventors: after the application was filed and not included in this • Griffith, David Andrew specification Old Saybrook, Connecticut 06475 (US) • Bronk, Brian Scott Gales Ferry, Connecticut 06335 (US) Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 002 802 B1 Printed by Jouve, 75001 PARIS (FR) EP 1 002 802 B1 Description [0001] This invention relates to dipeptide compounds which are growth hormone secretagogues and are useful for the treatment and prevention of osteoporosis and/or frailty, insulin resistance in mammals, congestive heart failure, 5 obesity, accelerating bone fracture repair and accelerating wound repair. Background of the Invention [0002] Growth hormone (GH), which is secreted from the pituitary gland, stimulates growth of all tissues of the body 10 that are capable of growing. In addition, growth hormone is known to have the following basic effects on the metabolic processes of the body: 1. Increased rate of protein synthesis in substantially all cells of the body; 2. Decreased rate of carbohydrate utilization in cells of the body; and 15 3. Increased mobilization of free fatty acids and use of fatty acids for energy. [0003] Deficiency in growth hormone results in a variety of medical disorders. In children, it causes dwarfism. In adults, the consequences of acquired GH deficiency include profound reduction in lean body mass and concomitant increase in total body fat, particularly in the truncal region. Decreased skeletal and cardiac muscle mass and muscle 20 strength lead to a significant reduction in exercise capacity. Bone density is also reduced. Administration of exogenous growth hormone has been shown to reverse many of the metabolic changes. Additional benefits of therapy have in- cluded reduction in LDL cholesterol and improved psychological well-being. This is described in U.S. Patent No. 60/050,764. [0004] International Patent Publication No. WO97/24369 also discloses the use of dipeptide compounds as growth 25 hormone secretagogues for the treatment or prevention of osteoporosis. [0005] International Patent Publication No. WO96/38471 relates to dipeptide compounds which are growth hormone releasing peptide mimetics and are useful for the treatment or prevention of osteoporosis. [0006] International Patent Publication No. WO96/35713 relates to dipeptide compounds which are growth hormone releasing mimetics and are useful in the treatment or prevention of osteoporosis. 30 Summary of the Invention [0007] The present invention provides novel chemical compounds of the following Formula I 35 40 or a pharmaceutically acceptable salt or prodrug thereof, 45 wherein: HET is a heterocyclic moiety selected from the group consisting of 50 55 2 EP 1 002 802 B1 5 10 15 20 25 e is 0 or 1; n and w are each independently 0, 1, or 2, provided that w and n cannot both be 0 at the same time; Y is oxygen or sulfur; 2 R is selected from the group consisting of hydrogen, fluoro, and (C1-C5)alkyl optionally substituted with 1-5 halo groups; 30 2A 6 6 6 6 R is selected from the group consisting of hydrogen, SX ,OX , -N(X )(X ), (C1-C8)alkyl, -(C0-C3)alkyl-(C1-C7) 1 cycloalkyl, and -(C0-C3)alkyl-A , where the alkyl groups and the cycloalkyl groups are optionally substituted with 6 6 6 6 6 1 6 hydroxy, thio, C(O)OX , C(O)N(X )(X ), SO2N(X )(X ), S(O)m(C1-C6)alkyl, C(O)A , C(O)(X ), CN or 1-5 halo groups; Q is a covalent bond or CR9R10; 35 Z is C=O, C=S or S(O)2; 2B 1 1 R is hydrogen, (C1-C8)alkyl, (C0-C3)alkyl-(C3-C8)cycloalkyl, -(C1-C4)alkyl-A or A ; where the alkyl groups and the cycloalkyl groups in the definition of R2B are optionally substituted with hydroxyl, C(O)OX6, -C(O)N(X6)(X6), 6 6 1 6 -N(X )(X ), -S(O)m(C1-C6)alkyl, C(O)A , -C(O)(X ), CF3, CN or 1, 2 or 3 halogen; 1 6 6 6 1 6 1 R is hydrogen, -CN, -(CH2)qN(X )C(O)X , -(CH2)qN(X )C(O)(CH2)t-A , -(CH2)qN(X )S(O)2(CH2)t-A , -(CH2)qN 40 6 6 6 6 1 6 6 6 6 6 (X )S(O)2X , -(CH2)qN(X )C(O)N(X )(CH2)tA , -(CH2)qN(X )C(O)N(X )(X ), -(CH2)qC(O)N(X )(X ), -(CH2)qC(O) 6 1 6 1 6 6 1 N(X )(CH2)t-A , -(CH2)qC(O)OX , -(CH2)qC(O)O(CH2)t-A , -(CH2)qOX , -(CH2)qOC(O)X ,-(CH2)qOC(O)(CH2)tA , 6 1 6 6 6 1 6 -(CH2)qOC(O)N(X )(CH2)t-A , -(CH2)qOC(O)N(X )(X ), -(CH2)qC(O)X , -(CH2)qC(O)(CH2)t-A , -(CH2)qN(X )C(O) 6 6 6 6 6 1 1 OX , -(CH2)qN(X )S(O)2N(X )(X ), -(CH2)qS(O)mX , -(CH2)qS(O)m(CH2)t-A , -(C1-C10)alkyl, -(CH2)t-A , 1 1 1 1 -(CH2)q-(C3-C7)cycloalkyl, -(CH2)q-Y -(C1-C6)alkyl, -(CH2)q-Y -(CH2)t-A or -(CH2)q-Y -(CH2)t-(C3-C7)cycloalkyl; 45 1 wherein the alkyl and cycloalkyl groups in the definition of R are optionally independently substituted with (C1-C4) alkyl, hydroxy, (C1-C4)alkoxy, carboxyl, -CONH2, -S(O)m(C1-C6)alkyl, -CO2(C1-C4)alkyl ester, 1 H-tetrazol-5-yl or 1, 2 or 3 fluoro groups; 1 6 6 6 6 Y is O, S(O)m, -C(O)NX -, -CH=CH-, -C;C-, -N(X )C(O)-, -C(O)NX -, -C(O)O-, -OC(O)N(X )- or -OC(O)-; 50 q is 0, 1, 2, 3 or 4, with the proviso that q cannot be 0 when (CH2)q, is attached to N or O; t is 0, 1, 2 or 3; m is 1 or 2; 3 1 1 R is selected from the group consisting of A ,(C1-C10)alkyl, -(C1-C6)alkyl-A ,-(C1-C6)alkyl-(C3-C7)cycloalkyl, 1 1 1 1 -(C1-C5)alkyl-X -(C1-C5)alkyl, -(C1-C5)alkyl-X -(C0-C5)alkyl-A and -(C1-C5)alkyl-X -(C1-C5)alkyl-(C3-C7)cycloalkyl; 55 3 3 where the alkyl groups in the definition of R are optionally substituted with - S(O)m(C1-C6)alkyl, -C(O)OX ,1,2, 3, 4 or 5 independently selected halo groups or 1, 2 or 3 independently selected -OX3 groups; 1 2 2 2 2 2 2 X is O, S(O)m, -N(X )C(O)-, -C(O)N(X )-, -OC(O)-, -C(O)O-, -CX =CX -,-N(X )C(O)O, - OC(O)N(X )- or -C;C-; 2 X for each occurrence is independently hydrogen, optionally substituted (C1-C6)alkyl or optionally substituted 3 EP 1 002 802 B1 (C3-C7)cycloalkyl, where the optionally substituted (C1-C6)alkyl and optionally substituted (C3-C7)cycloalkyl in the def- 2 3 3 inition of X are optionally independently substituted with -S(O)m(C1-C6)alkyl, -C(O)OX , 1 to 5 halo groups or 1-3 OX groups; 4 4 3 R is hydrogen, (C1-C6)alkyl or (C3-C7)cycloalkyl, or R is taken together with R and the carbon atom to which 5 they are attached and form (C5-C7)cycloalkyl, (C5-C7)cycloalkenyl, a partially saturated or fully saturated 4- to 8-mem- bered ring having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, or R4 and R3 can be taken together to form a bicyclic ring system consisting of a partially saturated or fully saturated 5- or 6-membered ring, fused to a partially saturated, fully unsaturated or fully saturated 5- or 6-membered ring, op- tionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; 10 4 4 4 4 X is hydrogen or (C1-C6)alkyl or X is taken together with R and the nitrogen atom to which X is attached and the carbon atom to which R4 is attached and form a five to seven membered ring; R6 is a bond or 15 20 a b a b , or -(CR R )a-E-(CR R )b-; a b where the -(CR R )a- group is attached to the carbonyl carbon of the amide group of the compound of Formula I and the -(CRaRb)b group is attached to the terminal nitrogen atom of the compound of Formula I; 25 E is -O-, -S-,-CH=CH-, 30 35 40 c c which is optionally substituted with halo, hydroxy, -N(R )(R ), (C1-C6)alkyl or (C1-C6)alkoxy; a b R and R are independently hydrogen, (C1-C6)alkyl, trifluoromethyl, phenyl or substituted (C1-C6)alkyl where 45 c c c the substituents are imidazolyl, naphthyl, phenyl, indolyl, p-hydroxyphenyl, -OR , S(O)mR , C(O)OR ,(C3-C7)cy- cloalkyl, -N(Rc)(Rc), -C(O)N(Rc)(Rc); or Ra and Rb may independently be joined to one or both of R7 or E (where E is other than O, S or -CH=CH-) to form an alkylene bridge between the terminal nitrogen and the alkyl portion of the Ra or Rb and the R7 or E group, wherein the bridge contains 1 to 8 carbon atoms; or Ra and Rb may be joined to one another to form a (C3-C7)cycloalkyl; 50 c R is hydrogen or (C1-C6)alkyl; a and b are independently 0, 1, 2 or 3, with the proviso that if E is -O- or -S-, y is other than 0 or 1 and with the further proviso that if E is -CH=CH-, y is other than 0; 5 5a 1 X and X are each independently selected from the group consisting of hydrogen,