MXPA01004800A - Crf receptor antagonists and methods relating thereto - Google Patents
Crf receptor antagonists and methods relating theretoInfo
- Publication number
- MXPA01004800A MXPA01004800A MXPA/A/2001/004800A MXPA01004800A MXPA01004800A MX PA01004800 A MXPA01004800 A MX PA01004800A MX PA01004800 A MXPA01004800 A MX PA01004800A MX PA01004800 A MXPA01004800 A MX PA01004800A
- Authority
- MX
- Mexico
- Prior art keywords
- carbon atoms
- alkyl
- methyl
- ethyl
- compound according
- Prior art date
Links
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Abstract
Compounds are disclosed which have utility in the treatment of a variety of disorders, including the treatment of disorders manifesting hypersecretion of CRF in warmblooded animals, including stroke. The compounds of this invention have structures (I):(a) wherein n, m, R, R1, R2, X and Ar are as defined herein, including stereoisomes and pharmaceutically acceptable salts thereof.
Description
ANTAGONISTS OF THE RECEIVER OF THE CORTICOTROPIN RELEASE FACTOR, CRF, AND METHODS RELATED THERETO
TECHNICAL FIELD
This invention relates generally to CRF receptor antagonists, and to methods for treating disorders through the administration of said antagonists to a warm-blooded animal with the need thereof.
BACKGROUND OF THE INVENTION
The first corticotropin releasing factor (CRF) was isolated from the hypothalamus of sheep and was identified as a peptide of amino acid 41 (Vale et al., Science 213: 1394-1397, 1981).
Subsequently, human and rat CRF sequences were isolated and determined to be identical, but different from sheep CRF at 7 of the 41 amino acid residues (Rivier et al., Proc. Nati, Acad. Sci. USA 80: 4851, 1983; Shibahara et al., EMBO J.
2: 775, 1983). It has been found that the CRF factor produces profound alterations in the function of the endocrine, nervous and immune system.
It is believed that the CRF factor is the main physiological regulator of the basal and tension release of the adrenocorticotropic hormone ("ACTH"), β-endorphin and other peptides derived from pro-opiomelanocortin ("POMC") of the anterior pituitary ( Vale et al., Science 213: 1394-1397, 1981). In summary, it is believed that the CRF factor initiates its biological effects by binding to a plasma membrane receptor, which has been found to be distributed through the brain (DeSouza et al., Science 224-1449-1451, 1984), pituitary (DeSouza et al., Methods Enzymol, 124: 560, 1986, Wynn et al., Biochem Biophys, Res. Comm. 110-602-608, 1983), adrenals (Udelsman et al., Nature 319: 147-150, 1986) and spleen (Webster, EL, and EB DeSouza, Endocrinology 122: 609-617, 1988). The CRF receptor is coupled to a GTP binding protein (Perrin et al., Endocrinology 118: 1171-1179, 1986) which mediates the stimulated increase by CRF factor in the intracellular production of cAMP (Bilezikjian, LM, and WW Vale , Endocrinology 113: 657-662, 1983). The receptor for CRF factor has now been cloned from rat brain (Perrin et al., Endo 133 (6): 3058-3061, 1993), and from human (Chen et al., PNAS 90 (19): 8967-8971, 1993; Vita et al., FEBS 335 (1): 1-5, 1993). This receptor is a 415 amino acid protein comprising 7 membrane expansion domains. An identity comparison between the rat and human sequences shows a high degree of homology (97%) at the amino acid level. In addition to this role to stimulate the production of ACTH and POMC, the CRF factor is also thought to coordinate many of the endocrine, autonomic and behavioral responses to stress, and may be involved in the pathophysiology of emotional disorders. In addition, it is believed that CRF is a key intermediary in the communication between the immune, central nervous, endocrine and cardiovascular systems (Crofford et al., J. Clin. Invest. 90: 2555-2564, 1992; Sapolsky et al., Science. 238-522-524, 1987; Tilders et al., Regul. Peptides 5: 77-84, 1982). In summary, the CRF factor seems to be one of the neurotransmitters of the central nervous system and plays a crucial role in the integration of the body's total response to stress. The administration of CRF factor directly to the brain produces behavioral, physiological and endocrine responses identical to those observed in an animal exposed in a stress-filled environment. For example, intracerebroventricular injection of the CRF factor results in behavioral activation (Sutton et al., Nature 297: 331, 1982), persistent activation of the electroencephalogram (Ehlers et al., Brain Res. 278: 332, 1983), stimulation of the sympathetic-medullary trajectory (Brown et al., Endocrinology 110: 928, 1982), an increase in heart rate and blood pressure (Fisher et al., Endocrinology 110: 222, 1982), an increase in oxygen consumption (Brown et al., Life Sciences 30: 207, 1982), alteration of gastrointestinal activity (Williams et al., Am. J. Physiol. 253: G582, 1982), suppression of food consumption (Levine et al., Neuropharmacology 22: 337, 1983), modification of sexual behavior (Sirinathsinghji et al., Nature 305: 232, 1983), and compromise of immune function (Irwin and others, Am. J. Physiol. 255: R744, 1988). In addition, clinical data suggest that CRF can be hypersecreted in the brain in depression, anxiety-related disorders, and anorexia nervosa. (DeSouza, Ann, Reports in Med. Chem. 25: 215-223, 1990). Accordingly, clinical data suggest that CRF receptor agonists may represent novel antidepressant and / or anxiolytic drugs that may be useful in the treatment of neuropsychiatric disorders by manifesting CRF factor hypertension. The first CRF receptor antagonists were peptides (see, for example, Rivier et al., U.S. Patent 4,605,642; Rivier et al., Science 224: 889, 1994). Although these peptides established that CRF receptor antagonists can attenuate pharmacological responses to the CRF factor, peptide CRF receptor antagonists have usual therapeutic disadvantages of peptide including lack of stability and limited oral activity. More recently, small molecule CRF receptor antagonists have been reported. For example, the substituted derivatives of 4-thio-5-oxo-3-pyrazoline (Abreu et al., US Patent 5,063,245) and the substituted derivatives of 2-aminothiazole (Courtemanche et al., Australian patent, AU-A-41399 / 93) have been reported as CRF receptor antagonists. It has been found that these particular derivatives are effective in inhibiting the binding of CRF factor to their receptor in the 1-10 μM scale, and the 0.1-10 μM scale, respectively. More recently, numerous small molecule CRF receptor antagonists have been proposed, including the compounds described in the following patent documents: WO 94/13643, WO 94/13644, WO 94/13661, WO 94/13676, WO 94 / 13677, WO 95/10506, WO 95/33750, WO 96/35689, WO 97/00868, WO 97/35539, WO 97/35580, WO 97/35846, WO 97/44038, WO 98/03510, WO 98 / 05661, WO 98/08846, WO 98/08847, WO 98/11075, WO 98/15543, WO 98/21200 and WO 98/29413. Due to the physiological importance of the CRF factor, the development of biologically active small molecules having an important binding activity of the CRF factor receptor and that are capable of antagonizing the CRF receptor remains a desired objective. Such CRF receptor antagonists may be useful in the treatment of endocrine, psychiatric and neurological conditions or diseases, including disorders related to stress in general. Although significant advances have been made in obtaining regulation of CRF factor through the administration of CRF receptor antagonists, there remains a need in the art for effective small molecule CRF receptor antagonists. There is also a need for pharmaceutical compositions containing said CRF receptor antagonists, as well as methods related to their use to treat, for example, stress-related disorders. The present invention satisfies these needs, and provides other related advantages.
COMPENDIUM OF THE INVENTION
In summary, this invention is generally directed to CRF receptor antagonists, and more specifically to CRF receptor antagonists having the following general structure (I):
including stereoisomers and their pharmaceutically acceptable salts, wherein m, n, X, R, R ,, R2 and Ar are as defined below. The CRF receptor antagonists of this invention have utility over a wide variety of therapeutic applications, and can be used to treat a variety of disorders or diseases, including stress-related disorders. Such methods include administering an effective amount of a CRF receptor antagonist of this invention, preferably in the form of a pharmaceutical composition, to an animal in need thereof. Accordingly, in another embodiment, pharmaceutical compositions are described which contain one or more CRF receptor antagonists of this invention in combination with a pharmaceutically acceptable carrier and / or diluent. These and other aspects of the invention will be apparent upon reference to the following detailed description. Up to this point, several references have been established herein, which describe in more detail certain procedures, compounds and / or compositions, and are hereby incorporated by reference in their entirety.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is generally directed to compounds useful as corticotropin releasing factor (CRF) receptor antagonists. In a first embodiment, the CRF receptor antagonists of this invention have the following structure (I):
including its stereoisomers and pharmaceutically acceptable salts thereof, wherein: n is 1 or 2; m is 0, 1, 2 or 3; X is N or CR '; R is an optional substituent which, in each occurrence, is independently alkyl of 1 to 6 carbon atoms, alkenyl of 3 to 6 carbon atoms, alkylidenyl of 1 to 6 carbon atoms, or alkyl of 1 to 6 carbon atoms -Ar; R 'is hydrogen, halogen or alkyl of 1 to 6 carbon atoms; Rn is -C (H) 0,? (R3) (R4); R2 is hydrogen or alkyl of 1 to 6 carbon atoms; R3 is hydrogen, keto, alkyl of 1 to 6 carbon atoms, mono or di (cycloalkyl of 3 to 6 carbon atoms) methyl, cycloalkyl of 3 to 6 carbon atoms, alkenyl of 3 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, alkyl of 1 to
6 carbon atoms -carbonyloxyalkyl of 1 to 6 carbon atoms, or alkyloxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, and R is hydrogen, Ar 1, alkyl of 1 to 6 carbon atoms-Ar 1 ,
OAr1, alkyl of 1 to 8 carbon atoms, alkyloxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, mono or di- (cycloalkyl of 3 to 6 carbon atoms) methyl, alkenyl of 3 to 6 carbon atoms, alkynyl of 3 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-Ar1, hydroxyalkyl of 1 to 6 carbon atoms , thienylalkyl of 1 to 6 carbon atoms, furanyl of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, morpholinyl, mono- or di- (alkyl of 1 to 6 atoms) carbon) aminoalkyl of 1 to carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, dialkyl of 1 to 6 carbon atoms, (alkyl of 1 to 6 carbon atoms-Ar1) amino, (alkyl of 1 to 6 carbon atoms) (Ar1) amino, alkylcarbonyl of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, alkylcarbonyloxy of 1 to 6 carbon atoms-alkyl or from 1 to 6 carbon atoms, sulfonylalkyl of 1 to 8 carbon atoms, C (= O) -alkyl of 1 to 6 carbon atoms, alkyl of 1 to 8 carbon atoms substituted with phthalimide, Ar1, OAr1, NHAr1 , C (= O) Ar \ C (= O) NHAr1 or -C (= O) NH2, or a radical of the formula - (alkanediyl of 1 to 6 carbon atoms) -Y- (CO) or,? - Ar1, where Y is O, NH or a direct bond or R3 and R4 taken together with the carbon atom to which they are attached form a cycloalkyl of 5 to 8 carbon atoms, a cycloalkenyl of 5 to 8 carbon atoms carbon, a heterocyclyl of 3 to 12 carbon atoms, phenyl, naphthyl or a cycloalkyl of 5 to 8 carbon atoms, fused to Ar1, each of which being optionally substituted with one or more substituents independently selected from alkyl of 1 to 6 carbon atoms; Ar is phenyl, naphthyl or a heterocyclyl of 3 to 12 aromatic carbon atoms, each being optionally substituted with 1, 2 or 3 substituents independently selected from halogen, alkyl of 1 to 6 carbon atoms, trifluoromethyl, O (trifluoromethyl), hydroxy, cyano, alkyloxy of 1 to 6 carbon atoms, phenoxy, benzoxy, alkylthio of 1 to 6 carbon atoms, nitro, amino, mono or di (alkyol of 1 to 6 carbon atoms) amino, 1 to 6 carbon atoms) (C 1-6 alkanoyl) amino, or piperidinyl, or wherein two substituents taken together are an alkylidinyl of 1 to 6 carbon atoms or an alkylidenyl of 1 to 6 carbon atoms having 1, 2 or 3 carbon atoms replaced with a heterogeneous atom individually selected from oxygen, nitrogen or sulfur; and Ar 1 is phenyl, naphthyl or a heterocycle of 3 to 12 aromatic carbon atoms, each of which is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, alkyl of 1 to 6 carbon atoms, alkyloxy of 1 to 6 carbon atoms, di (alkyl of 1 to 6 carbon atoms) amino, di (alkyl of 1 to 6 carbon atoms) aminoalkyl of 1 to 6 carbon atoms, trifluoromethylsulfonyl (alkyl of 1 to 6 carbon atoms) carbon), and alkyl of 1 to 6 carbon atoms substituted with morpholinyl. In the context of this invention, the foregoing terms have the meanings presented below. "Ceto" represents = O. "Alkyl of 1 to 6 carbon atoms or" alkyl of 1 to 8 carbon atoms "represents a straight or branched chain alkyl having 1 to 6 carbon atoms or 1 to 8 carbon atoms, respectively, such as methyl , ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, and the like. "Alkoxy of 1 to 6 carbon atoms" represents a group -O
(alkyl of 1 to 6 carbon atoms), such as methoxy, ethoxy, and the like. "Alkylthio of 1 to 6 carbon atoms) represents the group -S (alkyl of 1 to 6 carbon atoms), such as -SCH 3, -SCH 2 CH 3, and the like." Cycloalkyl of 3 to 6 carbon atoms "represents an alkyl cycloalkyl having 3 to 6 carbon atoms, including cyclopropyl, cyclopentyl, cyclopentyl and cyclohexyl "Cycloalkyl of 5 to 8 carbon atoms" represents a cyclic alkyl having from 5 to 8 carbon atoms, such as cyclopentyl, cyclohexyl, and the like. "Cycloalkenyl of 5 to 8 carbon atoms" represents a cyclic alkyl having from 5 to 8 carbon atoms and at least one double bond. "Alkenyl of 3 to 6 carbon atoms" represents a straight-chain alkyl or unsaturated branched chain having 3 to 6 carbon atoms, and having at least one double bond, such as propylenyl, 1-butenyl, 2-butenyl, 2-methylpropenyl, and the like. "Alkynyl of 3 to 6 atoms carbon "represents an unsaturated straight or branched chain alkyl which it has from 3 to 6 carbon atoms, and has at least one triple bond, such as propynyl, 1-butynyl, 2-butyne, 2-methylpropynyl, and the like. "Hydroxyalkyl of 1 to 6 carbon atoms" represents an alkyl of 1 to 6 carbon atoms substituted with at least one hydroxyl group, such as -CH 2 OH, -CH (OH) CH 3, and the like. "Mono- or di (cycloalkyl of 3 to 6 carbon atoms) methyl" represents a methyl group substituted with one or two cycloalkyl groups of 3 to 6 carbon atoms, such as cyclopropylmethyl, dicyclopropylmethyl, and the like. "Alkylcarbonyl of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms" represents an alkyl of 1 to 6 carbon atoms substituted with a -CO-alkyl group of 1 to 6 carbon atoms. "C 1 -C 6 -alkylcarbonyloxy-alkyl of 1 to 6 carbon atoms" represents an alkyl of 1 to 6 carbon atoms substituted with a -COO alkyl group of 1 to 6 carbon atoms. "C 1 -C 6 -alkoxy-C 1-6 -alkyl" represents an alkyl of 1 to 6 carbon atoms substituted with an -OC alkyl group of 1 to 6 carbon atoms. "Alkylthio of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms" represents an alkyl of 1 to 6 carbon atoms substituted with an alkyl-S group of 1 to 6 carbon atoms. "Sulfonyl (alkyl of 1 to 6 carbon atoms)" represents -SO2 (alkyl of 1 to 6 carbon atoms), such as -SO2 methyl and the like. "Mono or di (alkyl of 1 to 6 carbon atoms)" represents an amino substituted with an alkyl of 1 to 6 carbon atoms or with two alkyls of 1 to 6 carbon atoms, respectively. "(C 1 -C 6 -alkyl) (C 1 -C 6 -alkanoyl) amino" represents an amino substituted with an alkyl of 1 to 6 carbon atoms and an alkanoyl of 1 to 6 carbon atoms (i.e. , C (= O) (alkyl of 1 to 6 carbon atoms)). "Mono odi (any of 1 to 6 carbon atoms) aminoalkyl of 1 to 6 carbon atoms" represents an alkyl of 1 to 6 carbon atoms substituted with a mono or di (alkyl of 1 to 6 carbon atoms) Not me. "Alkylidene of 1 to 6 carbon atoms" represents an alkyl radical of 1 to 6 divalent carbon atoms, such as methylene (-CH2-), ethylene (-CH2CH2-), and the like. "Alkylidene of 1 to 6 carbon atoms having 1, 2 or 3 carbon atoms replaced with a heterogeneous atom individually selected from oxygen, nitrogen or sulfur" represents an alkylidenyl of 1 to 6 carbon atoms wherein 1, 2 or 3 Methylenyl groups (ie, "CH2") is replaced with O, N or S, such as -OCH2O-, -OCH2CH2O-, and the like. "Heterocycle of 3 to 12 carbon atoms" represents a ring made of more than one type of atom, and containing from 3 to 12 carbon atoms, such as pyridinyl, pyrimidinyl, furanyl, thienyl, imidazolyl, thiazolyl, pyrazolyl, pyridazinyl , pyrazinyl, triazinyl, (such as 1,3,5), pyrrolyl, thiophenyl, oxazolyl, isoxazolyl, pyrrolinyl, pyrrolidinyl, piperidinyl, and the like, as well as heterocyclic rings fused to phenyl to form a bicyclic ring, such as pyrrolidinophenyl, and Similar. "Halo or halogen" represents fluoro, chloro, bromo or iodo. As used in the context of this invention,GR.
represents -CH2CH2"or -CH = CH- optionally substituted with one or two substituents R (ie, when n = 1 and m = 0, 1 or 2), or -CH2CH2CH2- optionally substituted with 1, 2 or 3 substituents R ( that is, when n = 2 and m = 0, 1, 2 or 3.) Accordingly, representative compounds of this invention include (but are not limited to) compounds having the following structures (1-1), (I- 2), (I-3), (I-4), (I-5) and (I-6):
-i) (1-2) (1-3) (1-4) d-5) (1-6)
More specifically, and depending on the selection of the X portion, the representative CRF receptor antagonists of this invention include compounds having the following structures (la) and (Ib), respectively:
In a preferred embodiment, the receptor antagonists of the
CRFs of this invention have the structure (la). In another preferred embodiment, the CRF receptor antagonists of this invention have the structure (Ib), wherein R 'is hydrogen. Said compounds are represented by the following structures (I-1a), (1-1b), (l-4a) and (l-4b): (Ma) d-4b)
As noted above, Ri is -C (H) 0 (R3) (R4), which represents -CH (R3) (R4) and -C (R3) (R4). The representative modalities in this regard include the following portions R ^
Similarly, when R3 is keto, the representative R \ portions include the following:
O < R4
The representative R portions in this respect include -C (= O) R 4 1 -C (= O) OR 4, -C (= O) NH 2, -C (= O) NH (alkyl of 1 to 6 carbon atoms) and -C (= O) N (alkyl of 1 to 6 carbon atoms) (alkyl of 1 to 6 carbon atoms). In the embodiment wherein the groups R 3 and R 4 taken together form a cycloalkyl of 3 to 8 carbon atoms the resulting R-1 group has the structure:
Representative cycloalkyls of 3 to 8 carbon atoms include cyclopropyl, cyclopentyl and cyclohexyl, furthermore, when the cycloalkyl is from 3 to 8 carbon atoms is a cycloalkyl of 5 to 7 carbon atoms, optionally substituted with one or more alkyl groups of 1 to 6 carbon atoms, a representative R ^ portion has the following structure:
wherein R5 and R6 are the same or different and independently are selected from an alkyl of 1 to 6 carbon atoms, such as methyl or ethyl. Similary, in a modality in which the R3 and R groups of Ri taken together form a cycloalkyl of 5 to 8 carbon atoms fused to Ar, the resulting group R ^ has the structure:
including its optionally substituted analogs as defined above. In more specific embodiments of this invention, representative Ar groups of this invention include 2,4,6-trimethylphenyl, 2-chloro-4-methylphenyl, 2-chloro-4-methoxyphenyl, 2-bromo-4-methylphenyl, 2- methyl-4-chlorophenyl, 2-methyl-4-methyl-methyl, 2-bromo-4-isopropylphenyl, 2,4-dichlorophenyl, 2,6-dimethyl-4-bromophenyl, 4-chlorophenyl, 2,4-dimethoxyphenyl, 2,4-dimethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 2-methyl-4-methoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 2,4,6-trifluorophenyl, 2-methyl-4-N (ethyl) 2-phenyl, 2-bromo-4- (OCF3) phenyl, 4-dimethylamino-2-methyl-3-pyridinyl, 4-dimethylamino-6-methyl-2-pyridinyl, 4-dimethylamino 3-pyridinyl, 4-N (CH 3) (COCH 3) -phenyl, 3,4-methylenedioxyphenyl and 3,4-ethylenedioxyphenyl. Optional representative R groups of this invention include methyl, ethyl, n-propyl, iso-propyl, iso-butyl, = CH2 and = CHCH3. Representative R 'groups are hydrogen, fluoro, chloro, bromo, methyl and ethyl and preferably hydrogen. Representative R groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, neopentyl, and -CH (ethyl) 2, -CH (n-propyl) 2, -CH (n-butyl) 2, -CH2CH2OCH3, -CH (methyl) (CH2OCH3), -CH (ethyl) (CH2OCH3), -CH (n-propyl) (CH2OCH3), -CH (n-butyl) (CH2OCH3), -CH (tert-butyl)
(CH2OCH3), -CH (CH2OCH3) 2, -CH (benzyl) (CH2OCH3), -CH (4-chlorobenzyl) (CH2OCH3), -CH (CH2OCH3), -CH (CH2OCH3)
(CH2CH2SCH3), -CH (ethyl) (CH2Obenzyl), -CHC = CH, -CH (methyl) (ethyl), -CH (methyl) (n-propyl), -CH (methyl) (n-butyl), - CH (methyl) (n-pentyl), -CH (methyl) (CH2CH2CH2CH (CH3) 2), -CH (ethyl) (n-propyl), -CH (ethyl) (n-butyl), -CH (ethyl) (n-pentyl), -CH (n-propyl) (n-butyl), -CH (n-propyl) (n-pentyl), cyclopropyl, cyclobutyl, cyclohexyl, 2-methylcyclohexyl, 3-methylcyclohexyl, 1, 2, 3,4-tetrahydronaphthyl (1 and 2), benzyl, 2-chlorobenzyl, -CH (methyl) benzyl), -CH (ethyl) (benzyl), -CH (n-propyl) (benzyl), -CH (n- butyl) (benzyl), -CH2 (cyclopropyl), -CH2 (cyclobutyl), -CH2CH (methyl) CH2CH3, -CH2CH (ethyl) CH2CH3, -CHC (methyl) 3, -CH2CsCH, -CH2C (= O) ethyl, -C (= O) cyclopropyl, -C (= O) NHbenzyl, -C (= O) methyl, -C (= O) benzyl, -C (= O) phenyl, -C (= O) ethyl), - C (= O) CH2C (= O) Oetyl, -C (= O) CH (phenyl) ethyl, C (= O) pyridyl, -C (= O) (4-N, N-dimethylamino) phenyl, -C (= O) CH2Omethyl, -C (= O) CH (ethyl) 2, -C (= O) n-butyl, -C (= O) CH2CH2 (methyl) 2, -C (= O) n-propyl, -C (= O)
CH2CH2phenyl, -CH2pyridyl, -CH2CH2NHphenyl, -CH2CH2C (= O) Oethyl, -CH2CH2CH2phenyl, -CH2CH2-N-phthalimide, -CH2CH2CH2C (= O) Oethyl, -CH2CH2Oethyl, -CH2CH (methyl) 2, -CH2C (= O) Oethyl, -CH2C (= O) pyrrodinophenyl, -CH2CH2Ophenyl, -CH2CH2CH2CH2-N-phthalimide, -CH2C (= O) Ot-butyl, -CH2CH2CH (methyl) 2, -CH2C (= O) NH2, -CH2- 4- (SO2CH3) phenyl, -CH2CH2propyl and benzyl. Representative R 2 groups include methyl, ethyl and hydrogen, and preferably methyl. The compounds of the present invention can be prepared through organic synthesis techniques, including the methods described in more detail in the examples, and can generally be used as the free base. Alternatively, the compounds of this invention can be used in the form of acid addition salts. The acid addition salts of the free base amino compounds of the present invention can be prepared by methods well known in the art, and can be formed from organic and inorganic acids. Suitable organic acids include maleic, fumaric, benzoic, ascorbic, succinic, methanesulfonic, acetic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, aspartic, stearic, palmitic, glycolic, glutamic, and benzenesulfonic acids . Suitable inorganic acids include hydrochloric, hydrobromic, sulfuric, phosphoric and nitro acids. More specifically, the compounds of structure (I) can be made according to the procedures set forth in Examples 1 and 2, as well as through the following general reaction scheme:
Reaction Scheme
The effectiveness of a compound as an antagonist of the CRF receptor can be determined through various assay methods. Suitable CRF antagonists of this invention are capable of inhibiting the specific binding of CRF to its receptor and antagonizing activities associated with the CRF factor. A compound of structure (I) can be analyzed for activity as a CRF factor antagonist through one or more generally accepted assays for this purpose, including (but not limited to) the assays described by DeSouza et al., (J Neuroscience 7:88, 1987) and Battaglia et al., (Synapse 1: 572, 1987). As mentioned above, suitable CRF factor antagonists include compounds that demonstrate affinity to the CRF receptor. The affinity of the CRF receptor can be determined through binding studies that measure the activity of a compound to inhibit the binding of a radiolabelled CRF factor (eg, [125l] tyrosine CFR) to its receptor (eg, prepared receptors from membranes of the rat cerebral cortex). The radioligand binding assay described by DeSouza et al. (Supra, 1987) provides an assay for determining the affinity of a compound for the CRF factor receptor. Said activity is typically calculated from the IC 50 value as the concentration of a compound necessary to displace 50% of the radiolabelled ligand from the receptor, and is reported as a "K" value, calculated by the following equation:
K, = ± Cso. 1 + L / KD
Where L = radioligand, KD = radioligand affinity for receptor (Cheng and Prusoff, Biochem Pharmacol 22: 3099, 1973). In addition to inhibiting the binding of the CRF receptor, an activity of the CRF receptor antagonist of the compound can be established through the ability of the compound to antagonize an activity associated with the CRF factor. For example, it is known that the CRF factor stimulates several biochemical processes, including the activity of adenylate cyclase. Therefore, the compounds can be evaluated as antagonists of the CRF factor by their ability to antagonize the activity of adenylate cyclase stimulated with the CRF factor, for example, by measuring the levels of cAMP. The adenylate cyclase activity assay stimulated by the CRF factor described by Battaglia et al., (Supra, 1987) provides an assay to determine the ability of a compound to antagonize the activity of the CRF factor. Accordingly, the CRF factor receptor antagonist activity can be determined through assay techniques, which generally include an initial binding assay (as described by DeSouza (supra, 1987)) followed by a protocol for classification of cAMP (as described by Battaglia (supra, 1987)). With reference to the binding affinities of the CRF factor receptor, the CRF factor receptor antagonists of this invention have a K value of less than 10 μM. In a preferred embodiment of this invention, a CRF factor receptor antagonist has a K value, less than 1 μM, and most preferably less than 0.25 μM (ie 250 nM). As set out in more detail below, the representative compounds of this invention were analyzed by the method of Example 4. Preferred compounds have a K value, less than 1 μM and are compounds with the numbers (1-1) at (I -25) and (I-29) to (I-33). Highly preferred compounds having a K value of less than 250 nM are compounds with the numbers (1-1) to (1-14), (1-16) to (I-25) and (I-29) to (1-32). The CRF receptor receptor antagonists of the present invention demonstrate activity at the CRF receptor site, and can be used as therapeutic agents for the treatment of a wide variety of disorders or diseases including endocrine, psychiatric and neurological disorders or diseases. More specifically, the CRF factor receptor antagonists of the present invention may be useful for the treatment of physiological conditions or disorders arising from hypersecretion of the CRF factor. Since the CRF factor is believed to be a pivotal neurotransmitter that activates and coordinates the behavioral and automatic endocrine responses to stress, the CRF factor receptor antagonists of the present invention can be used to treat neuropsychiatric disorders. Neuropsychiatric disorders, which may be treatable through the CRF factor receptor antagonists of this invention, include affective disorders such as depression; disorders related to anxiety such as generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, abnormal aggression, cardiovascular abnormalities such as unstable angina and reactive hypertension; and eating disorders such as anorexia nervosa, bulimia and irritable bowel syndrome. Antagonists of the CRF factor may also be useful for treating immune suppression induced by stress associated with various disease states, as well as stroke. Other uses of the CRF factor antagonists of this invention include the treatment of inflammatory conditions (such as rheumatoid arthritis, uveitis, asthma, inflammatory bowel disease, and gastrointestinal motility) Cushing's disease, childhood asthma, epilepsy, and other attacks in both children as adults, and various aspects of substance abuse and withdrawal (including alcoholism).
In another embodiment of the invention, pharmaceutical compositions are described which contain one or more CRF factor receptor antagonists. For the purpose of administration, the compounds can be formulated as pharmaceutical compositions. The pharmaceutical compositions of the present invention comprise a CRF factor receptor antagonist of the present invention (ie, a compound of structure (I)) and a pharmaceutically acceptable carrier and / or diluent. The CRF receptor antagonist is present in the composition in an amount that is effective to treat a particular disorder, ie, in an amount sufficient to achieve the activity of the CRF receptor antagonist and preferably with acceptable toxicity to the patient. Preferably, the pharmaceutical compositions of the present invention can include a CRF factor receptor antagonist in an amount of 0.1 mg to 250 mg per dose, depending on the route of administration, and most preferably from 1 mg to 60 mg. The appropriate concentrations and doses can be readily determined by one skilled in the art. The pharmaceutically acceptable carrier and / or diluents are familiar to those skilled in the art. For compositions formulated as liquid solutions, acceptable carriers and / or diluents include saline and sterile water, and optionally may include antioxidants, pH regulators, bacteriostats, and other common additives. The compositions can also be formulated as pills, capsules, granules, or tablets, which contain, in addition to a CRF receptor antagonist, diluent, surface active and dispersing agents, binders and lubricants. One skilled in the art can further formulate the CRF receptor antagonist in an appropriate manner, and in accordance with accepted practices, such as those described in Remington's Pharmaceutical Sciences, Gennaro, Ed. Mack Publishing Co., Easton, PA 1990). In another embodiment, the present invention provides a method for treating a variety of disorders or diseases, including endocrine, psychiatric and neurological disorders or diseases. Such methods include administering a compound of the present invention to a warm-blooded animal in an amount sufficient to treat the disorder or disease. Such methods include the systemic administration of a CRF receptor antagonist of this invention, preferably in the form of a pharmaceutical composition. As used herein, systemic administration includes oral and parenteral methods of administration. For oral administration, suitable pharmaceutical compositions of the CRF receptor antagonists include powders, granules, pills, tablets and capsules, as well as liquids, syrups, suspensions and emulsions. These compositions may also include flavors, preservatives, suspending agents, thickeners and emulsifiers, and other pharmaceutically acceptable additives. For parenteral administration, the compounds of the present invention may be prepared in aqueous solutions for injection, which may contain, in addition to the CRF receptor antagonist, pH regulators, antioxidants, bacteriostats, and other additives commonly employed in said solutions. As mentioned above, the administration of a compound of the present invention can be used to treat a wide variety of disorders or diseases. In particular, the compounds of the present invention can be administered to a warm-blooded animal for the treatment of depression, anxiety disorder, panic disorder, obsessive-compulsive disorder, abnormal aggression, unstable angina, reactive hypertension, anorexia nervosa, bulimia, irritable bowel syndrome, stress-induced immune suppression, stroke, inflammation, Cushing's disease, infantile spasms, epilepsy, and substance abuse or withdrawal. The examples are provided for purposes of illustration and not limitation.
EXAMPLES
The CRF receptor antagonists of this invention can be prepared by the methods described in Examples 1-2. Example 3 describes representative compounds of this invention. Example 4 presents a method for determining the receptor binding activity (K), and Example 5 describes an assay for classifying the compounds of this invention for the adenylate cyclase activity stimulated by the CRF factor.
EXAMPLE 1 Synthesis of Representative Compounds (IA)
8
Compound (4) A solution of 4,6-dichloro-2-methyl-5-nitropyridine (3; J. Chem.
Soc. 1954, 3836) (2:23 g, 11 mmol) in 30 ml of EtOH at -30 ° C was treated with 1-ethylpropylamine (870 mg, 10 mmol) in 8 ml of EtOH and the reaction mixture was stirred at -30 ° C for 1 hour and then warmed to room temperature. The volatiles were evaporated and the residue was partitioned between water and EtOAc. The organic layer was dried (sodium sulfate), evaporated, purified by flash chromatography (silica) to give compound (4).
Compound (5) A solution of compound (4) (2.07 g, 8 mmol) in 15 ml of acetonitrile was treated with 2,4,6-trimethylaniline (1.35 g, 10 mmol) at room temperature, then triethylamine (1.52 g) was introduced. g, 15 mmol). The reaction mixture was stirred at room temperature for 2 hours. The volatiles were evaporated and the residue was partitioned between brine and EtOAc. The organic layer was dried (sodium sulfate), evaporated, purified by flash chromatography (silica) to give compound (5).
Compound (6) Compound (5) (2.14 g, 6 mmol) was dissolved in 20 ml of 1: 1 dioxane / water, and treated with 5 ml of concentrated aqueous ammonia hydroxide. Sodium hydrosulfite (3.12 g, 18 mmol) was added in small batches for 1 hour and the solution was stirred at room temperature for 8 hours. The reaction mixture was partitioned between brine and EtOAc. The organic layer was dried (sodium sulfate), evaporated, purified by flash chromatography (silica) to give compound (6).
Compound (7) A mixture of compound (6) (6.54 mg, 2 mmol) and 500 mg of triethylamine in 10 ml of dry THF was treated with triphosgene (2.17 mg, 0.73 mmol), and the reaction mixture was stirred at room temperature. environment for 1 hour. The precipitates were filtered and the filtrate was evaporated, and the residue was partitioned between brine and EtOAc. The organic layer was dried (sodium sulfate), evaporated, purified by flash chromatography (silica) to give compound (7).
Compound (8) Compound (7) (353 mg, 1 mmol) in 5 ml of DMF was treated with NaH / 129 mg, 3 mmol), 60% in oil) at room temperature). Then, 1,2-dibromoethane (654 mg, 3 mmol) was added to the reaction mixture and stirred for 10 hours. The reaction mixture was partitioned between water and EtOAc. The organic layer was dried (sodium sulfate), evaporated, purified by flash chromatography (silica) to give compound (8). LCMS 380 (MH +).
Compound (9) A solution of compound (8) (38 mg, 0.1 mmol) in 2 ml of toluene was treated with an activated manganese dioxide catalyst (100 mg) at reflux for 16 hours. The catalyst was removed by filtration through a pad of Celite and the filtrate was evaporated to dryness and purified by preparative TLC (silica gel) with ethyl acetate-hexane (1: 1) to provide the compound ( 9).
EXAMPLE 2 Synthesis of Representative Compounds of the Structure (IB)
The compounds of structure (Ib) can be made through the same synthetic route as described above in Example 1, but using the corresponding pyridine for compound (1) instead of pyrimidine. For example, representative compounds of this invention can be made through the following reaction scheme:
? Four. Five
EXAMPLE 3 Synthesis of Representative Compounds
Other representative compounds of this invention were made through the general reaction scheme described above and / or through the procedures of Examples 1 and 2, and are presented in the following Table.
TABLE Representative Compounds
(1-17) 7.61 (d, 1 H), 7.49 (d, 1 H), 7.31 (dd, 1 H), 6.27 (s, 1 H), 4.06-4.13 (dt, 1 H), 3.89-3.97 (dt, 1 H), 3.71-3.78 (m, 1H), 3.42 (t, 2H), 2.41 (s, 3H), 1.53-1.63 (m, 4H), 1.28-1.39 (m, 4H), 0.91- 0.97 (m, 6H). (1-18) 7.39-7.45 (m, 1 H), 6.10-7.076 (m, 3H), 6.31 (s, 1 H), 4.04 (t, 2H), 3.78-3.87 (m, 4H), 3.52 (m, t, 2H), 2.54 (s, 3H), 1.59-1.67 (m, 4H), 1.21-1.42 (m, 4H), 0.95 t, 6H) (1-19) 7.09-7.21 (m, 3H), 6.23 (s, 1H), 3.93-4.15 (m, 2H), 3.71-3.77 (m, 1 H), 3.93 (t, 2H), 2.39 (s, 3H), 2.35 (s, 3H), 1.49-1.65 ( m, 4H), 1.26-1.41 (m, 4H), 0.90- 0.96 (m, 6H) (I-20) 6.99 (dd, 1 H), 7.00 (d, 1 H), 6.72 (d, 1 H) , 6.07 (s, 1 H), 5.82 (s, 2H), 3.81 (t, 2H), 3.51-3.61 (m, 1H), 3.20 (t, 2H), 2.26 (s, 3H), 1.33-1.50 ( m, 4H), 1.07-1.21 (m, 4H), 0.75 (t, 6H). (1-21) 7.35 (s, 1H), 7.277-7.281 (m, 2H), 6.27 (s, 1H), 3.95-4.07 (m, 2H), 3.63 (pentet, 1H), 3.41 (t, 2H) , 2.41 (s, 3H), 2.25 (s, 3H), 1.59-1.66 (m, 4H), 1.19- 1.36 (m, 4H), 0.87-0.97 (m, 6H) (I-22) 7.35 (s, 1 H), 7.277-7.281 (m, 2H), 6.27 (s, 1 H), 3.93-4.06 (m, 2H), 3.51-3.61 (7, 1H), 3.41 (t, 2H), 2.41 (s, 3H), 2.25 (s, 3H), 1.59-1.70 (7, 4H), 0.95 (t, 3H), 0.92 (t, 3H) (I-23) 7.35 (s, 1H), 7.275-7.28 (7 2H ), 6.26 (s, 1H), 3.91-4.1 (7, 2H), 3.6-3.75 (7, 1H), 3.41 (t "2H), 2.41 (s, 3H), 2.24 (s, 3H), 1.54- 1.68 (7, 4H), 1.30-1.42 (7, 2H), 0.90-0.97 (7, 6H) (I-24) 7.35 (s, 1 H), 7.278-7.282 (m, 2H), 6.26 (s, 1H), 3.92-4.10 (m, 2H), 3624 (pentet, 1H), 3.41 (t, 2H), 2.41 (s, 3H), 2.25 (s, 3H), 1.54-1.68 (m, 4H), 1.20 - 1.38 (m, 6H), 0.84-0.97 (m, 6H) (1-25) 7.35 (s, 1 H), 7.28 (s, 2H), 62.4 (s, 1 H), 3.92-4.10 (m, 2H), 3.72 (pentet, 1 H), 3.40 (t, 2H), 2.40 (s, 3H), 2.24 (s, 3H), 1.56-1.62 (m, 4H), 1.26-1.38 (m, 6H), 0.86-0.97 (m, 6H) (I-26) 7.01 (d, 2H), 6.42 (t, 1 H), 6.26 (s, 1 H), 4.00 (t, 2h), 3.80 (s, 6H), 3.69-3.80 (m, 1H), 3.38 (t, 2H), 2.45 (s; 3H), 1.46-1.66 (m, 4H), 1.23-1.38 (m, 4H), 0.92 (t, 6H). (I-27) 6.79 (d, 1 H), 6.29 (s, 1 H), 3.97 (t, 2H), 3.69-3.79 (m, 1 H), 3.37 (t, 2H), 2.51 (s, 3H) ), 2.47 (d, 3H), 1.51-1.75 (m, 4H), 1.25-1.37 (m, 4H), 0.83-0.94 (m, 6H). (I-28) 7.72 (d, 2H), 7.33-7.38 (m, 2H), 7.06-7.14 (m, 5H), 4.00 (t, 2H), 3.70-3.80 (m, 1H), 3.39 (t, 2H), 2.45 (s, 3H), 1.47-1.65 (m, 4H), 1.25-1.39 (m, 4H), 0.93 (t, 6H). (I-29) 8.57 (d, 1H), 7.95 (dd, 1H) < 6.86 (d, 1H), 6.26 (s, 1H), 4.00 (t, 2H), 3.91 (s, 3H), 3.70-3.79 (m, 1H), 3.39 (t, 2H), 2.43 (s, 3H) , 1.51-1.67 (m, 4H), 1.25-1.38 (m, 4H), 0.92 (t, 6H). (I-30) 0.92 (t, 6H), 1.25-1.38 (m, 4H), 1.51-1.62 (m, 4H), 2.42 (s, 3H), 3.12 (s, 6H), 3.38 (t, 2H) , 3.71-3.77 (m, 1 H), 3.99 (t, 2H), 6.24 (s, 1 H), 6.63-8.47 (m, 3H); MS (Cl) m / z 409.20 (MH +). (1-31) 7.66 (d, 2H), 7.01 (d, 2H), 6.2 (s, 1H), 4.18 (dd, 1H), 3.84 (s, 3H), 3.54- 3.72 (m, 5H), 3.38 -3.44 (m, 1H), 3.37 (s, 3H), 2.45 (s, 3H), 1.31-1.73 (m, 2H), 1.00 (t, 3H) (I-32) 7.62 (d, 2H), 7.01 (d, 2H), 6.23 (s, 1H), 4.23 (dd, 1H), 3.84 (s, 3H), 3.60-3.81 (m, 5H), 3.31-3.40 (m, 1 H), 2.44 (s, 3H), 1.5-1.72 (m, 2H), 1.01 (t, 3H) (1-33) 7.94 (d, 2H), 7.30 (d, 2H), 6.29 (s, 1H), 4.01 (t, 2H) , 3.76 (s, 1H), 3.41 (t, 2H), 3.28 (s, 3H), 2.48 (s, 3H), 1.96 (t, 3H), 1.49-1.68 (m, 4H), 1.25-1.37 (m , 4H), 0.94 (t, 6H) (I-34) 7.64 (d, 2H), 7.01 (d, 2H), 6.2 (s, 1H), 4.18 (dd, 1H), 3.84 (s, 3H), 3.56-3.74 (m, 3H), 3.22-3.32 (m, 1H), 2.55-2.65 (m, 6H), 2.45 (s, 3H), 1.52-1.73 (m, 2H), 0.98-1.07 (m, 9H) ) (1-35) d 8.16 (d, 2H), 8.05 (d, 2H), 6.28 (s, 1H), 4.00t, 2H), 3.93 (s, 3H), 3.71-3.81 (m, 1H), 3.39 (t, 2H), 2.47 (s, 3H), 1.52-1.65 (m, 4H), 1.28-1.39 (m, 4H), 0.92 (t, 6H). (I-36) d 8.60 (d, 1H), 7.82 (dd, 1H), 7.74 (d, 1H), 6.29 (s, 1H), 3.99 (t, 2H), 3.73- 3.78 (m, 1H), 3.87 (t, 2H), 2.48 (s, 3H), 1.51-1.62 (m, 4H), 1.25-1.38 (m, 4H), 0.92 (t, 6H). (I-37) d 8.08 (s, 4H), 6.29 (s, 1H), 4.00 (t, 2H), 3.71-3.81 (m, 1H), 3.97 (t, 2H), 2.62 (s, 3H), 2.47 (s, 3H), 1.52-1.62 (m, 4H), 1.22-1.39 (m, 4H), 0.93 (t, 6H). (I-38) d 7.72 (d, 2H), 7.60 (d, 2H), 6.27 (s, 1H), 4.00 (t, 2H), 3.68-3.82 (m, 1H), 3.48 (s, 6H), 3.39 (t, 3H), 2.45 (s, 3H), 1.54-1.63 (m, 4H), 1.24-1.38 (m, 4H), 1.08 (t, 3H), 0.93 (t, 3H).EXAMPLE 4 CRF Factor Receptor Binding Activity
The compounds of this invention can be evaluated for CRF receptor binding activity through a standard radioligand binding assay as generally described by DeSouza et al., (J. Neurosci, 7: 88-100, 1987). Using several radiolabelled CRF factor ligands, the assay can be used to evaluate the binding activity of the compounds of the present invention with any subtype of CRF factor receptor. In summary, the binding assay involves the displacement of a ligand of the radiolabeled CRF factor from the CRF receptor. More specifically, the binding assay was performed in 1.5 ml Eppendorf tubes using approximately 1 x 106 cells per tube stably transfected with human CRF receptors. Each tube received approximately 0.1 ml of the assay pH regulator (for example saline regulated at its pH with Dulbecco's phosphate, 10 mM magnesium chloride, and 20 μM bacitracin) with or without unlabeled sauvagine, urotensin I or CRF ( final concentration, 1 μM) to determine non-specific binding, 0.1 ml of sheep [1 5l] trosse-CRF (final concentration of ~ 200 pM or approximately the KD value as determined through the Scatchard analysis) and 1.0 ml of a suspension of cell membranes containing the CRF receptor. The mixture was incubated for 2 hours at 22 ° C followed by separation of the bound and free radioligan by centrifugation. After two washes of the pellets, the tubes were cut just above the pellet and verified in a gamma counter for radioactivity at approximately 80% efficiency. The radioligand binding data can be analyzed using the LIGAND non-linear least squares fitting program of Munson and Rodbard (Anal. Biochem. 107: 220, 1990).
EXAMPLE 5 Adenylate Cyclase Activity Estimated by CRF
The compounds of the present invention can also be evaluated through various functional tests. For example, the compounds of the present invention can be classified for the activity of adenylate cyclase stimulated by CRF. An assay for the determination of CRF-stimulated adenylate cyclase activity can be performed as is generally described by Battaglia et al. (Synapse 1: 572, 1987), with modifications to adapt the assay to whole cell preparations. More specifically, the standard assay mixture may contain the following in a final volume of 0.5 ml: 2 mM L-glutamine, 20 mM HEPES, and 1 mM IMBX in DMEM pH buffer. In stimulation studies, whole cells with the transfected CRF receptors were placed in 24-well plates and incubated for 1 hour at 37 ° C with various concentrations of CRF-related and unrelated peptides, in order to establish the pharmacological rank-order profile of the particular receptor subtype. After incubation, the medium was aspirated, the cavities were rinsed once moderately with a fresh medium, and the medium was aspirated. To determine the amount of intracellular cAMP, 300 μl of a 95% ethanol solution and 20 mM aqueous hydrochloric acid were added to each well, and the resulting suspensions were incubated at -20 ° C for 16 to 18 hours. The solution was removed to 1.5 ml Eppendorf tubes and the wells were washed with an additional 200 μl of ethanol / aqueous hydrochloric acid and combined with the first fraction. The samples were lyophilized and then resuspended with 500 μl of pH buffer sodium acetate. The measurement of cAMP in the samples was performed using an individual antibody kit from Biomedical Technologies Inc. (Stoughton, MA). For the functional determination of the compounds, a single concentration of CRF or related peptides was incubated causing a stimulation of 80% of the cAMP production together with several concentrations of competing compounds (10"12 to 10" 6 M). It will be appreciated that, although specific embodiments of the invention have been described for the purpose of illustration, various modifications can be made without departing from the spirit and scope of the invention. Accordingly, the invention is not limited, except as by the appended claims.
Claims (23)
1. - A compound that has the following structure: and its stereoisomers and pharmaceutically acceptable salts thereof, wherein: n is 1 or 2; m is 0, 1, 2 or 3; X is N or CR '; R is an optional substituent which, in each occurrence, is independently alkyl of 1 to 6 carbon atoms, alkenyl of 3 to 6 carbon atoms, alkylidenyl of 1 to 6 carbon atoms, or alkyl of 1 to 6 carbon atoms -Ar; R 'is hydrogen, halogen or alkyl of 1 to 6 carbon atoms; R is -C (H) or,? (R3) (R), -CH2C = CH, or -CH2C (= O) NH2; R2 is hydrogen or alkyl of 1 to 6 carbon atoms; R3 is hydrogen, keto, alkyl of 1 to 6 carbon atoms, mono or di (cycloalkyl of 3 to 6 carbon atoms) methyl, cycloalkyl of 3 to 6 carbon atoms, alkenyl of 3 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms-carbonyloxyalkyl of 1 to 6 carbon atoms, 0 alkyloxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, and R 4 is hydrogen, Ar 1, alkyl of 1 to 6 carbon atoms-Ar 1,
OAr1, alkyl of 1 to 8 carbon atoms, alkyloxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, mono or di- (cycloalkyl of 3 to 6 carbon atoms) methyl, alkenyl of 3 to 6 carbon atoms, alkynyl of 3 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms-Ar1, hydroxyalkyl of 1 to 6 carbon atoms, thienylalkyl of 1 to 6 carbon atoms, furanilakyl of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, morpholinyl, mono od i- (to Iq uilo of 1 to 6 carbon atoms) aminoalkyl of 1 to carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, dialkyl of 1 to 6 carbon atoms, (alkyl of 1 to 6 carbon atoms-Ar1) amine, (alkyl of 1 to 6 carbon atoms) (Ar1) amino, alkylcarbonyl of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, alkylcarbonyloxy of 1 to 6 carbon atoms-alkyl of 1 to 6 carbon atoms, sulfonylalkyl of 1 to 8 carbon atoms, C (= O) -alkyl of 1 to 6 carbon atoms, alkyl of 1 to 8 carbon atoms substituted with phthalimide , Ar1, OAr1, NHAr1, C (= O) Ar \ C (= O) NHAr1 or -C (= O) NH2, or a radical of the formula - (alkanediyl of 1 to 6 carbon atoms) -Y- ( CO) 0,? - Ar1, where Y is O , NH or a direct bond or R3 and R4 taken together with the carbon atom to which they are attached form a cycloalkyl of 5 to 8 carbon atoms, a cycloalkenyl of 5 to 8 carbon atoms, a heterocyclyl of 3 to 12 carbon atoms, carbon, phenyl, naphthyl or a cycloalkyl of 5 to 8 carbon atoms, fused to Ar 1, each of which being optionally substituted with one or more substituents independently selected from alkyl of 1 to 6 carbon atoms; Ar is phenyl, naphthyl or a heterocycle of 3 to 12 aromatic carbon atoms, each being optionally substituted with 1, 2 or 3 substituents independently selected from halogen, alkyl of 1 to 6 carbon atoms, trifluoromethyl, O (trifluoromethyl), hydroxy, cyano, alkyloxy of 1 to 6 carbon atoms, phenoxy, benzoxy, alkylthio of 1 to 6 carbon atoms, nitro, amino, mono or di (alkyl of 1 to 6 carbon atoms) amino, (alkyl of 1 to 6 carbon atoms) (alkanoyl of 1 to 6 carbon atoms) amino, or piperidinyl, or wherein two substituents taken together are an alkylidinyl of 1 to 6 carbon atoms or an alkylidenyl of 1 to 6 carbon atoms having 1, 2 or 3 carbon atoms replaced with a heterogeneous atom individually selected from oxygen, nitrogen or sulfur; and Ar 1 is phenyl, naphthyl or a heterocycle of 3 to 12 aromatic carbon atoms, each of which is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, alkyl of 1 to 6 carbon atoms, alkyloxy of 1 to 6 carbon atoms, di (alkoxy of 1 to 6 carbon atoms) amino, di (alkoxy of 1 to 6 carbon atoms) aminoalkyl of 1 to 6 carbon atoms, trifluoromethylsulfonyl (alkyl of 1 to 6 carbon atoms), and alkyl of 1 to 6 carbon atoms substituted with morpholinyl. 2. The compound according to claim 1, wherein n is 1.
3. The compound according to claim 2, which has the structure:
4. - The compound according to claim 2, which has the structure:
5. The compound according to claim 1, wherein n is 2.
6. The compound according to claim 5, having the structure:
7. - The compound according to claim 1, wherein m is 0.
8. The compound according to claim 7, having the structure:
9. - The compound according to claim 7, which has the structure:
10. - The compound according to claim 1, wherein m is 1.
11. The compound according to claim 10, having the structure:
12. - The compound according to claim 10, having the structure:
13. - The compound according to claim 10, having the structure:
14. - The compound according to claim 1, wherein X is CR 'and R' is hydrogen.
15. The compound according to claim 1, wherein X is N.
16. The compound according to claim 1, wherein R is alkyl of 1 to 6 carbon atoms.
17. The compound according to claim 1, wherein R is methyl or ethyl.
18. The compound according to claim 1, wherein R is ethyl.
19. The compound according to claim 1, wherein Ar is 2,4,6-trimethylphenyl, 2-chloro-4-methylphenyl, 2-chloro-4-methoxyphenyl, 2-bromo-4-methylphenyl, 2- methyl-4-chlorophenyl, 2-methyl-4-bromophenyl, 2-bromo-4-isopropylphenyl, 2,4-dichlorophenyl, 2,6-dimethyl-4-bromophenyl, 4-chlorophenyl, 2,4-dimethoxyphenyl, 2, 4-dimethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-methyl-4-methoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 4-trifluoromethylphenyl, 2,4,6-trifluorophenyl, 2- methyl-4-N (ethyl) 2-phenyl, 2-bromo-4- (OCF 3) phenyl, 4-dimethylamino-2-methylpyridin-3-yl, 4-dimethylamino-6-methyl-2-pyridin-3-yl, 4 -dimethylamino-pyridin-3-ylo, 4-N (CH 3) (Ac) phenyl, 5-methylisoxazol-3-yl, 3,4-methylenedioxyphenyl and 3,4-ethylenedioxyphenyl.
20. The compound according to claim 1, wherein Ar is 2,4,6-trimethylphenyl, 2-methyl-4-chlorophenyl, 2-chloro-4-methylphenyl, 2,4-dichlorophenyl, 2,6- dimethyl-4-bromophenyl, 2-bromo-4-methylphenyl, 4-methoxyphenyl or 4-chlorophenyl.
21. The compound according to claim 1, wherein R is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, and -CH (ethyl) 2, -CH (n-propyl) 2, -CH (n-butyl) 2, -CH 2 CH 2 OCH 3, -CH (methyl) (CH 2 OCH 3), -CH (ethyl) (CH 2 OCH 3), -CH ( n-propyl) (CH2OCH3), -CH (n-butyl) (CH2OCH3), -CH (tert-butyl) (CH2OCH3), -CH (CH2OCH3) 2, -CH (benzyl) (CH2OCH3), -CH (4 -chlorobenzyl) (CH2OCH3), -CH (CH2OCH3) (CH2CH2SCH3), -CH (ethyl) (CH2Obenzyl), -CH (methyl) (ethyl), -CH (methyl) (n-propyl), -CH (methyl) (n-butyl), -, CH (methyl) (n-pentyl), -CH (methyl) (CH2CH2CH2CH (CH3) 2), -CH (ethyl) (n-propyl), -CH (ethyl) (n- butyl), -CH (ethyl) (n-pentyl), -CH (n-propyl) (n-butyl), -CH (n-propyl) (n-pentyl), cyclopropyl, cyclobutyl, cyclohexyl, 2-methylcyclohexyl, 3-methylcyclohexyl, 1,2,3,4-tetrahydronaphthyl (1 and 2), benzyl, 2-chlorobenzyl, -CH (methyl) benzyl), -CH (ethyl) (benzyl), -CH (n-propyl) ( benzyl), -CH (n-butyl) (benzyl), -CH2 (cyclopropyl), -CH2 (cyclobutyl), -CH2CH (methyl) CH 2CH3, -CH2CH (ethyl) CH2CH3, -CH2C (methylo) 3, -CH2C (= O) ethyl, -C (= O) cyclopropyl, -C (= O) NHbenzyl, -C (= O) methyl, -C (= O) benzyl, -C (= O) phenyl, -C (= O) ethyl, -C (= O) CH2C (= O) Oethyl, -C (= O) CH (phenyl) ethyl,
C (= O) pyridyl, -C (= O) (4-N, N-dimethylamino) phenyl, -C (= O) CH2Omethyl, -C (= O) CH (ethyl) 2, -C (= O) n-butyl, -C (= O) CH2CH2 (methyl) 2, -C (= O) n-propyl, -C (= O) CH2CH2phenyl, -CH2pyridyl, -CH2CH2NHphenyl, -CH2CH2C (= O) Oethyl, - CH2CH2CH2phenyl, -CH2CH2-N-phthalimide, -CH2CH2CH2C (= O) Oethyl, -CH2CH2Oethyl, -CH2CH (methyl) 2, -CH2C (= O) Oethyl, -CH2C (= O) pyrrodinophenyl, -CH2CH2Ophenyl, -CH2CH2CH2CH2- N-phthalimide, -CH2C (= O) Ot-butyl, -CH2CH2CH (methylo) 2, -CH2C (= O) NH2, -CH2-4- (SO2CH3) phenol, -CH2CH2propyl and benzyl. 22. The compound according to claim 1, wherein R is -CH (ethyl) 2, -CH (n-propyl) 2, -CH (ethyl) (n-butyl) or -CH (ethyl) (n-pentyl). 23. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier. 24. A method for treating a disorder that manifests hypersecretion of the CRF factor in a warm-blooded animal with the need thereof, which comprises administering to the animal an effective amount of the pharmaceutical composition of the claim
23. 25. The method according to claim 24, wherein the disorder is apoplexy. 26. The method according to claim 24, wherein the disorder is depression, anxiety disorder, panic disorder, obsessive-compulsive disorder, abnormal aggression, unstable angina, reactive hypertension, anorexia nervosa, bulimia, irritable bowel syndrome , immune suppression induced by tension, inflammation Cushing's disease, abuse or withdrawal of substances, infantile spasms, or epilepsy.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US09/190,958 | 1998-11-12 | ||
| US09/400,744 | 1999-09-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA01004800A true MXPA01004800A (en) | 2002-06-05 |
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