Use of estrogen antagonists and estrogen agonists in inhibiting pathological conditions

A method of inhibiting a pathological condition which is susceptible or partially susceptible to inhibition by an estrogen, antiestrogen or estrogen agonist, which comprises administering to a mammal in need of inhibition of said pathological condition selected from the group consisting of uterine cancer, adjuvant breast cancer, breast disorders, male breast cancer, migraine, incontinence, vaginal atrophy, bladder infection, senile gynecomastia, diabetes, hyperglycemia, failure of wound healing, melanoma, impotence, inflammatory bowel disease, CNS and GI disorders caused by an excess of tackykinins, decreased libido, immune system disorders, decreased fertility, pulmonary hypertensive disease, acne, seborrhea, autoimmune disease, Turner's syndrome, alopecia, hirsutism, disorders related to an excess of neurokinin and obsessive-compulsive disorders including smoking and alcohol abuse, an effective amount of a compound of formula I 15

• wherein:
• A is selected from CH2 and NR;
• B, D and E are independently selected from CH and N;
• Y is
• (a) phenyl, optionally substituted with 1-3 substituents independently selected from R4;
• (b) naphthyl, optionally substituted with 1-3 substituents independently selected from R4;
• (c) C3-C8 cycloalkyl, optionally substituted with 1-2 substituents independently selected from R4;
• (d) C3-C8 cycloalkenyl, optionally substituted with 1-2 substituents independently selected from R4;
• (e) a five membered heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NR2— and —S(O)n—, optionally substituted with 1-3 substituents independently selected from R4;
• (f) a six membered heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NR2— and —S(O)n— optionally substituted with 1-3 substituents independently selected from R4;
• or
• (g) a bicyclic ring system consisting of a five or six membered heterocyclic ring fused to a phenyl ring, said heterocyclic ring containing up to two heteroatoms selected from the group consisting of —O—, —NR2—, and —S(O)n—, optionally substituted with 1-3 substituents independently selected from R4;
• Z1 is
• (a) —(CH2)p W(CH2)q—;
• (b) —O(CH2)p CR5R6—;
• (c) —O(CH2)pW(CH2)q;
• (d) —OCHR2CHR3—;
• or
• (e) —SCHR2CHR3—;
• G is
• (a) —NR7R8;
• (b) 16
• wherein n is 0, 1 or 2;
• m is 1, 2 or 3;
• Z2 is —NH—, —O—, —S—, or —CH2—;
• optionally fused on adjacent carbon atoms with one or two phenyl rings and, optionally independently substituted on carbon with one to three substituents and, optionally, independently on nitrogen with a chemically suitable substituent selected from R4;
• or
• (c) a bicyclic amine containing five to twelve carbon atoms, either bridged or fused and optionally substituted with 1-3 substituents independently selected from R4;
• Z1 and G in combination may be 17
• W is
• (a) —CH2—;
• (b) —CH═CH—;
• (c) —O—;
• (d) —NR2—;
• (e) —S(O)n—;
• (f) 18
• (g) —CR2(OH)—;
• (h) —CONR2—;
• (i) —NR2CO—;
• (j) 19
• or
• (k) —C≡C—;
• R is hydrogen or C1-C6 alkyl;
• R2 and R3 are independently
• (a) hydrogen;
• or
• (b) C1-C4 alkyl;
• R4 is
• (a) hydrogen;
• (b) halogen;
• (c) C1-C6 alkyl;
• (d) C1-C4 alkoxy;
• (e) C1-C4 acyloxy;
• (f) C1-C4 alkylthio;
• (g) C1-C4 alkylsulfinyl;
• (h) C1-C4 alkylsulfonyl;
• (i) hydroxy (C1-C4)alkyl;
• (j) aryl (C1-C4)alkyl;
• (k) —CO2H;
• (I) —CN;
• (m) —CONHOR;
• (n) —SO2NHR;
• (o) —NH2;
• (p) C1-C4 alkylamino;
• (q) C1-C4 dialkylamino;
• (r) —NHSO2R;
• (s) —NO2;
• (t) -aryl;
• or
• (u) —OH;
• R5 and R6 are independently C1-C8 alkyl or together form a C3-C10 carbocyclic ring;
• R7 and R8 are independently
• (a) phenyl;
• (b) a C3-C10 carbocyclic ring, saturated or unsaturated;
• (c) a C3-C10 heterocyclic ring containing up to two heteroatoms, selected from —O—, —N— and —S—;
• (d) H;
• (e) C1-C6 alkyl;
• or
• (f) form a 3 to 8 membered nitrogen containing ring with R5 or R6;
• R7 and R8 in either linear or ring form may optionally be substituted with up to three substituents independently selected from C1-C6 alkyl, halogen, alkoxy, hydroxy and carboxy;
• a ring formed by R7 and R8 may be optionally fused to a phenyl ring;
• e is 0, 1 or 2;
• m is 1, 2 or 3;
• n is 0, 1 or 2;
• p is 0, 1, 2 or 3;
• q is 0, 1, 2 or3;
• and optical and geometric isomers thereof;
• and nontoxic pharmacologically acceptable acid addition salts, N-oxides, esters, and quaternary ammonium salts thereof.