AP860A

AP860A - Dipeptide compounds which are growth hormone secretegoques.

Info

Publication number: AP860A
Application number: APAP/P/1999/001555A
Authority: AP
Inventors: Philip A Carpino; Jardine Paul A Dasilva; Bruce A Lefker; John A Ragan
Original assignee: Pfizer
Priority date: 1995-12-28
Filing date: 1999-05-27
Publication date: 1999-08-06
Also published as: SA97170581B1; BR9612465A; CN1206422A; CA2241725A1; US6278000B1; IL138910A0; IS4758A; UA66754C2; AU7585096A; KR100320167B1; HUP9901246A3; BG64055B1; DK0869968T3; PL327634A1; CA2241725C; CO4480108A1; HRP960618B1; ES2285715T3; OA10702A; SK285678B6

Abstract

This invention is directed to compounds of the formula and the pharmaceutically-acceptable salts thereof, where the substituents are as defined in the Specification, which are growth hormone secretogogues and wnich increase the level of endogenous growth hormone. The compounds of this invention are useful for the treatment and prevention of osteoporosis, congestive heart failure, frailty associated with aging, obesity; accelerating bone fracture repair, attenuating protein catabolic response after a major operation, reducing cachexia and protein loss due to chronic illness, accelerating wound healing, or accelerating the recover/ of burn patients or patients having undergone major surgery; improving muscle strength, mobility, maintenance of skin thickness, metabolic homeostasis or renal homeostasis. The compounds of the present invention are also useful in treating osteoporosis when used in combination with; a bisphosphonate compound such as alendronate; estrogen, premarin, and optionally progesterone; an estrogen agonist or antagonist; or calcitonin, and pharmaceutical compositions useful therefor Further, the present invention is directed to pharmaceutical compositions useful fcr increasing the endogenous production or release of growth hormone in a human or other animal which comprises an effective amount of a compound of the present invention and a growth hormone secretagogue selected from GHRP-6, Hexarelin. GHRP-1, growth hormone releasing factor (GRF), IGF-1, IGF-2 or B-HT92Q The invention is also directed to intermediates useful in the preparation of compouncs of formula I.

Description

HETEROCYCLIC CQMEQ.UNPS

This invention relates to dipeptide compounds which are growth hormone secretagogues and are useful for the treatment and prevention of osteoporosis.

Background of the.lnyen.tion

Growth hormone (GH), which is secreted from the pituitary gland, stimulates growth of all tissues of the body that are capable of growing. In addition, growth hormone is known to have the following basic effects on the metabolic process 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; 3. Increased mobilization of free fatty acids and use of fatty acids for energy.

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 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 included reduction in LDL cholesterol and improved psychological well-being.

In cases where increased levels of growth hormone were desired, the problem was generally solved by providing exogenous growth hormone or by administering an agent which stimulated growth hormone production and/or release. In either case the peptidyl nature of the compound necessitated that it be administered by injection. Initially the source of growth hormone was the extraction of the pituitary glands of cadavers. This resulted in an expensive product, and carried with it the risk that a disease associated with the source of the pituitary gland could be transmitted to the recipient of the growth hormone (e.g., Jacob-Creutzfeld disease). Recently, recombinant growth hormone has become available which, while no longer carrying any risk of disease transmission, is still a very expensive product which must be given by injection or by a nasal spray.

Most GH deficiencies are caused by defects in GH release, not primary defects in pituitary synthesis of GH. Therefore, an alternative strategy for normalizing serum GH levels is by stimulating its release from somatotrophs. Increasing GH secretion can be achieved by stimulating or inhibiting various neurotransmitter systems in the brain and hypothalamus. As a result, the development of synthetic growth hormone-releasing agents to stimulate pituitary GH secretion are being pursued, and may have several advantages over expensive and inconvenient GH replacement therapy. By acting along physiologic regulatory pathways, the most desirable agents would stimulate pulsatile GH secretion, and excessive levels of GH that have been associated with the undesirable side effects of exogenous GH administration would be avoided by virtue of intact negative feedback loops.

Physiologic and pharmacologic stimulators of GH secretion include arginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, vasopressin, and insulin induced hypoglycemia, as well as activities such as sleep and exercise, indirectly cause growth hormone to be released from the pituitary by acting in some fashion on the hypothalamus perhaps either to decrease somatostatin secretion or to increase the secretion of the known secretagogue growth hormone releasing factor (GHRF) or an unknown endogenous growth hormone-releasing hormone or all of these.

Other compounds have been developed which stimulate the release of endogenous growth hormone such as analogous peptidyl compounds related to GRF or the peptides of U.S. Patent 4,411,890. These peptides, while considerably smaller than growth hormones are still susceptible to various proteases. As with most peptides, their potential for oral bioavailability is low. WO 94/13696 refers to certain spiropiperidines and homologues which promote release of growth hormone. Preferred compounds are of the general structure shown below.

WO 94/11012 refers to certain dipeptides that promote release of growth hormone. These dipeptides have the general structure

where L is

The compounds of WO 94/11012 and WO 94/13696 are reported to be useful in the treatment of osteoporosis in combination with parathyroid hormone or a bisphosphonate.

Summary of the Invention

This invention provides compounds of the formula:

the racemic-diastereomeric mixtures and optical isomers of said compounds and the ’ pharmaceutically-acceptable salts and prodrugs thereof, wherein 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; R1 is hydrogen, -ON, -(CH2)qN(X6)C(0)X6, -(CH2)qN(X6)C(O)(CH2)t-A1, -(CH2)qN(X6)SO2(CH2)t-A1, -(CH2)qN(X6)SO2X6, -(CH2)qN(X5)C(0)N(X6)(CH2)t-A1, -(CH2)qN(X6)C(O)N(X6)(X6),-(CH2)qC(O)N(X6)(X6), -(CH2)qC(0)N(X6)(CH2)t-A1, -(CH2)qC(O)OX6, -(CH2)qC(0)0(CH2)t-A1, -(CH2)qOX6, -(CH2)qOC(O)X6, -(CH2)qOC(O)(CH2)t-A1,-(CH2)qOC(O)N(X6)(CH2)t-A1,-(CH2)qOC(O)N(X6)(X6), -(CH2)qC(O)X6, -(CH2)qC(O)(CH2)t-A1, -(CH2)qN(X6)C(O)OX6, -(CH2)qN(X6)SO2N(X6)(X6), -(CH2)qS(O),/ -(CH2)qS(O)m(CH2)rA1, -(C-i-G-io)alkyl, -(CH2)t-A , -(CH2)q-(C3-C7)cycloalkyl, -(CH2)q-Y1-(Ci-C5)a!kyl, -(CH2)q-Y1-(CH2)t-A1 or -(CH2)q-Y1-(CH2)r(C3-C7)cycioaikyl; where the alkyl and cycloalkyl groups in the definition of R1 are optionally substituted with (CrC4)alkyl, hydroxyl, (CrC4)alkoxy, carboxyl, -CONH2, -SiO^CvCJalkyl, -C02(C1-C4)alkyl ester, 1 H-tetrazol-5-yl or 1, 2 or 3 fluoro; Y1 is O, S(O)m, -C(O)NX6-, -CH=CH-, -0=0-, -N(X6)C(O)-, -C(O)NX6-, -0(0)0-, -OC(O)N(X6)- or -OC(O)-;

q is Ο, 1, 2, 3 or 4; t is 0, 1, 2 or 3; said (CH2)q group and (CH2)t group may each be optionally substituted with hydroxyl, (CrCJalkoxy, carboxyl, -CONH2, -S(O)m(Ci-C6)alkyl, -CO2(C1-C4)alkyl ester, 1H-tetrazol-5-yl, 1, 2 or 3 fluoro, or 1 or 2 (Cr CJalkyl; R2 is hydrogen, (CrCejalkyl, -(C0-C3)alkyl-(C3-C8)cycloalkyl, -<C1-C4)alkyl-A1 or A1; where the alkyl groups and the cycloalkyl groups in the definition of R2 are optionally substituted with hydroxyl, -C(O)OX6, -C(O)N(X6)(X6), -N(XS)(X6), -S(O)m(C1-C6)alkyl, -C(O)A1, -C(O)(X6), CF3, CN or 1, 2 or 3 halogen; R3 is A1, (CrCwJalkyl, -(C^Cejalkyl-A1, -(C1-C6)alkyl-(C3-C7)cycloalkyl, -(CrCsjalkyl-X’-iCrCsjalkyl, -(CrCsjalkyl-X^Co-Csjalkyl-A1 or -(CrCsJalkyl-X^CrCsjalkyl-iCjj-CTjcycloalkyl; I» where the alkyl groups in the definition of R3 are optionally substituted with, -S(O)m(CrC6)alkyl, -C(O)OX3, 1, 2, 3, 4 or 5 halogens, or 1, 2 or 3 OX3; X1 is O, S(O)m, -N(X2)C(O)-, -C(O)N(X2)-, -OC(O)-, -C(O)O-, -cx2=cx2-, -N(X2)C(O)O-, -OC(O)N(X2)- or -C=C-; R4 is hydrogen, (Ci-C6)alkyl or (C3-C7)cyeloalkyl, or R4 is taken together with R3 and the carbon atom to which they are attached and form (C5-C7)cycloalkyl, (C5-C7)cycloalkenyl, a partially saturated or fully saturated 4- to δ-membered ring having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, or is 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, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; X4 is hydrogen or (C-|-C6)alkyl or X4 is taken together with R4 and the nitrogen atom to which X4 is attached and the carbon atom to which R4 is attached and form a five to seven membered ring; R6 is a bond or is

where a and b are independently 0, 1, 2 or 3;

X5 and X5a are each independently selected from the group consisting of hydrogen, trifluoromethyl, A1 and optionally substituted (C1-C6)alkyl; the optionally substituted (O',-Ce)alkyl in the definition of X5 and X5a is optionally substituted with a substituent selected from the group consisting of A1, OX2, -3(0)^(0,-C6)alkyl, -C(0)0X2, (C3-C7)cycloalkyl, -N(XZ)(X2) and -C(O)N(X2)(X2); or the carbon bearing X5 or X5a forms one or two alkylene bridges with the nitrogen atom bearing R7 and R8 wherein each alkylene bridge contains 1 to 5 carbon atoms, provided that when one alkylene bridge is formed then X5 or X5a but not both may be on the carbon atom and R7 or R8 but not both may be on the nitrogen atom and further provided that when two alkylene bridges are formed then X5 and X5a cannot be on the carbon atom and R7 and R8 cannot be on the nitrogen atom; or X5 is taken together with X5a and the carbon atom to which they are attached and form a partially saturated or fully saturated 3- to 7-membered ring, or a partially saturated or fully saturated 4- to 8-membered ring having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen; or Xs is taken together with X5a and the carbon atom to which they are attached and form a bicyclic ring system consisting of a partially saturated or fully saturated 5- or 6-membered ring, optionally having 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; Z1 is a bond, 0 or N-X2, provided that when a and b are both 0 then Z1 is not N-X2 or O; R7 and R8 are independently hydrogen or optionally substituted (Ci-C6)alkyl; where the optionally substituted (C,-C6)alkyl in the definition of R7 and R8 is optionally independently substituted with A1, -0(0)0-(0,-C6)alkyl, -S(O)m(C,-C6)alkyl, 1 to 5 halogens, 1 to 3 hydroxy, 1 to 3 -0-0(0)(0,-C10)alkyl or 1 to 3 (C,-C6)alkoxy; or R7 and R8 can be taken together to form -(CH2)r-L-(CH2)r-; where L is C(X2)(X2), S(0)m or N(X2); A1 for each occurrence is independently (C5-C7)cycloalkenyl, phenyl or a partially saturated, fully saturated or fully unsaturated 4- to 8-membered ring optionally having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, a bicyclic ring system consisting of a partially saturated, fully unsaturated or fully saturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; A1 for each occurrence is independently optionally substituted, in one or optionally both rings if A1 is a bicyclic ring system, with up to three substituents, each substituent independently selected from the group consisting of F, Cl, Br, I, OCF3, OCF2H, CF3, CH3, OCH3, -OX6, -C(O)N(X6)(X6), -C(O)OX6, oxo, (C1-C6)alkyl, nitro, cyano, benzyl, -SiO^CvCgJalkyl, 1 H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halophenyl, methylenedioxy, -N(X6)(X6), -N(X6)C(O)(X6), -SO^X6)^6), -N(X6)SO2-phenyl, -N(X6)SO2X6, -CONX11X12, -SO2NX11X12, -NX6SO2X12, -NX6CONX11X12, -NX6SO2NX11X12, -NX6C(O)X12, imidazolyl, thiazolyl or tetrazolyl, provided that if A1 is optionally substituted with methylenedioxy then it can only be substituted with one methylenedioxy; where X11 is hydrogen or optionally substituted (CrC6)alkyl; the optionally substituted (C-|-C6)alkyl defined for X11 is optionally independently substituted with phenyl, phenoxy, (Cr C6)alkoxycarbonyl, -S(O)m(Ci-C6)alkyl 1 to 5 halogens, 1 to 3 hydroxy, 1 to 3 (CrCio)alkanoyloxy or 1 to 3 (Cr^alkoxy; X12 is hydrogen, (C-|-C6)alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, provided that when X12 is not hydrogen, X12 is optionally substituted with one to three substituents independently selected from the group consisting of Cl, F, CH3, OCH3, OCF3 and CF3; or X11 and X12 are taken together to form -(CH2)r-L1-(CH2)r-; L1 is C(X2)(X2), 0, S(0)m or N(X2); r for each occurrence is independently 1, 2 or 3; X2 for each occurrence is independently hydrogen, optionally substituted (Ci-C6)alkyl, or optionally substituted (C3-C7)cycloalkyl, where the optionally substituted (CrC6)alkyl and optionally substituted (C3-C7)cycloalkyl in the definition of X2 are optionally independently substituted with -S(O)m(C1-C6)alkyl, -C(O)OX3, 1 to 5 halogens or 1 to 3 OX3; X3 for each occurrence is independently hydrogen or (CpCsJalkyl; X6 is independently hydrogen, optionally substituted (C-|-C6)alkyl, (C2-C6)halogenated alkyl, optionally substituted (C3-C7)cycloalkyl, (C3-C7)-halogenatedcycloalkyl, where optionally substituted (C^CeJalkyl and optionally substituted (C3-C7)cycloalkyl in the definition of X6 is optionally independently substituted by 1 or 2 (C1-C4)alkyl, hydroxyl, (C-i-C4)alkoxy, carboxyl, CONH2, -SiOjn/CrCgjalkyl, carboxylate (Cr C4)alkyl ester, or 1H-tetrazol-5-yl; or when there are two X6 groups on one atom and both Xs jare independently (C-|-C6)alkyl, the two (Ci-C6)alkyl groups may be optionally joined and, together with the atom to which the two X6 groups are attached, form a 4- to 9- membered ring optionally having oxygen, sulfur or NX7; X7 is hydrogen or (Ci-C6)alkyl optionally substituted with hydroxyl; and m for each occurrence is independently 0, 1 or 2; with the proviso that: X6 and X12 cannot be hydrogen when it is attached to C(O) or SO2 in the form C(O)X6, C(O)X12, SO2X6 or SO2X12; and when R6 is a bond then L is N(X2) and each r in the definition -<CH2)r-L-(CH2)r- is independently 2 or 3. A preferred group of compounds, designated the “A Group’, contains those compounds having the formula I as shown hereinabove wherein X4 is hydrogen; R4 is hydrogen or methyl; R7 is hydrogen or (Ci-C3)alkyl; R8 is hydrogen or (CrC3)alkyl optionally substituted with one or two hydroxyl groups; R is

where Z is a bond and a is 0 or 1; X5 and X5a are each independently hydrogen, trifluoromethyl, phenyl, optionally substituted (CvCgjalkyl;

where the optionally substituted (Ci-C6)alkyl is optionally substituted with OX2, imidazolyl, phenyl, indolyf, p-hydroxyphenyl, (C5-C7)cycloalkyl, -S(O)m(CrC6)alkyl, -N(X2)(X2) or -C(O)N(X2)(X2); or X5 and R7 are taken together to form a (C^Csjalkylene bridge, and the other substituents not defined for the “A Group” compounds are as defined for formula (I) hereinabove. A group of compounds, which is preferred among the “A Group” of compounds, designated the “B Group”, contains those compounds of the “A Group", having the formula I as shown hereinabove, wherein b is 0; X5 and X5a are each independently hydrogen, (CrC^alkyl or hydroxy(C1-C3)alkyl; R3 is selected from the group consisting of 1-indolyl-CH2-, 2-indolyl-CH2-, 3-indolyl-CH2-, 1-naphthyl-CH2-, 2-naphthyl-CH2-, 1-benzimidazolyl-CH2-, 2-benzimidazolyl-CH2-, phenyl-(C-|-C4)alkyl-, 2-pyridyl-(C1-C4)alkyl-, 3-pyridyl-(C-i-C4)alkyl-, 4-pyridyl-(CvC4)alkyl-, phenyl-CH2-S-CH2-, thienyl-(Ci-C4)alkyi-, phenyl-(C0-C3)alkyl-O-CH2-, phenyl-CH2-O-phenyl-CH2-, and 3-benzothienyl-CH2-; where the aryl portion(s) of the groups defined for R3 are optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of methylenedioxy, F, Ci, CH3, OCH3i OCF3, OCF2H and CF3. A group of compounds, which is preferred among the “B Group” of compounds, designated the “C Group”, contain those compounds of the “B Group”, having the formula I as shown hereinabove, wherein R4 is hydrogen; a is 0; n is 1 or 2; w is 0 or 1; X5 and X5a are each independently, hydrogen, methyl or hydroxymethyl, provided that when X5 is hydrogen then X5a is not hydrogen; R7 and R8 are each hydrogen; and R3 is phenyl-CH2-O-CH2-, phenyl-CH2-S-CH2-, 1-naphthyl-CH2-, 2-naphthyl-CH2-, phenyl-(CH2)3- or 3-indolyl-CH2-; where the aryl portion of the groups defined for R3 is optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of fluoro, chloro, methyl, OCH3, OCF2H, OCF3 and CF3. A group of compounds, which is preferred among the “C Group' of compounds, designated the “D Group’, contains those compounds of the “C Group", having the formula I as shown hereinabove, wherein R1 is -(CH2)t-A1, -(CH2)q-(C3-C7)cycloalkyl or (C1-C10)alkyl; where A1 in the definition of R1 is optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of fluoro, chloro, methyl, OCH3, OCF2H, OCF3 and CF3; the cycloalkyl and alkyl groups in the definition of R1 are optionally substituted with (Ci-C4)alkyl, hydroxyl, (C1-C4)alkoxy, carboxyl, CONH2, -S(O)m(C1-C6)alkyl, -CO2(C1-C4)alkyl ester, 1 H-tetrazol-5-yl or 1 to 3 fluoro; Y is O; R2 is hydrogen, -(C0-C3)alkyl-(C3-C8)cycloalkyl, ohenyl or (G^CsJalkyl where the (C-|-Ca)alkyl group is optionally substituted with hydroxyl, -CF3 or 1 to 3 halogen. A group of compounds, which is preferred among the “D Group" of «* compounds, designated the Έ Group”, contains those compounds of the “D Group” wherein w is 0 and n is 1.

Another group of compounds, which is preferred among the “D Group” of compounds, designated the “F Group”, are those compounds of the “D Group”, having the formula I as shown hereinabove, wherein e is 0; n and w are each 1; R1 is-(CH2)t-A1; where A1 in the definition of R1 is phenyl, thienyl, thiazolyl, pyridyl or pyrimidyl which is optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of F, Cl, Me, OMe, CF3, OCF3 and OCF2H; t is 0, 1 or 2; and R3 is phenyl-CH2-O-CH2-, phenyl-(CH2)3- or 3-indolyl-CH2-, where the aryl portion is optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of F, Cl, Me, OMe, CF3, OCF3 or OCF2H. A group of compounds, which is preferred among the “F Group" of compounds, designated the “G Group”, contains those compounds of the “F Group", having the formula I as shown hereinabove, wherein X5 and X5a are each methyl; R1 is -CH2-phenyl, -CH2-4-fluoro-phenyl, -CH2-pyridyl or -CH2-thiazolyl and R2 is hydrogen, methyl, ethyl, t-butyl or -CH2CF3.

Claims

Original document published without claims.